Capsules and capsule coatings for gastric residence dosage forms

Abstract

To provide a novel gastric residence system.SOLUTION: Provided are gastric residence dosage forms comprising: a gastric residence system in a folded configuration; a capsule encapsulating the gastric residence system in a folded configuration; and a coating on the capsule, where the gastric residence dosage form is configured to release the gastric residence system in a stomach of a patient, allowing the gastric residence system to assume an open configuration. The coating on the capsule includes a polymer, an anti-tacking agent, and / or a hydration aid.SELECTED DRAWING: Figure 5A-C

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 821,352, filed March 20, 2019, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to capsules and capsule coatings, and more particularly to capsules and capsule coatings for gastroretentive dosage forms. [Background technology]

[0003] A gastroretentive system is a delivery system for a therapeutic agent that can remain in the stomach for a period of days to weeks or even longer, during which the therapeutic agent can be eluted from the gastroretentive system for absorption in the gastrointestinal tract. A gastroretentive system is typically designed to be administered in a capsule to reach the patient's stomach. The encapsulated gastroretentive system is swallowed or introduced into the stomach by an alternative method of administration (e.g., feeding tube or stomach tube). Once the capsule dissolves in the stomach, the gastroretentive system remains in the stomach and expands or unfolds to a size that resists passage through the pyloric valve for the desired residence time (3 days, 7 days, 2 weeks, etc.). Once the desired residence time has passed, the expanded or unfolded dosage form may become dissociated or otherwise characterized by a reduced effective size (e.g., due to increased ability to soften and disintegrate to smaller sizes) and thereby pass through the pyloric valve and be expelled from the patient. Summary of the Invention

[0004] Capsules and capsule coatings for gastroretentive systems are provided. Methods for preparing gastroretentive dosage forms using the capsules and / or capsule coatings provided herein are also provided. In particular, the capsules and capsule coatings provided herein can be used to ensure that the gastroretentive system is deployed at a location within the gastrointestinal tract (i.e., in the stomach) at a given time. For example, the capsules and capsule coatings provided herein can minimize the risk of the gastroretentive system deploying too early (e.g., in the esophagus) and causing blockage. The capsules and capsule coatings provided herein may also minimize the possibility of the gastroretentive system passing through the stomach and deploying late in the gastrointestinal tract (i.e., intestines). Furthermore, the capsules and capsule coatings provided herein minimize the risk of the gastroretentive dosage form passing through the gastrointestinal tract without deploying at all. In each of these possible events, the therapeutic agent is not delivered to the patient as intended.

[0005] The capsules and capsule coatings provided herein may include a sheath or band used to restrain the gastroretentive system in a folded configuration. In some embodiments, the restrained gastroretentive system may be encapsulated in a capsule to form a gastroretentive dosage form. Some gastroretentive dosage forms may include a reverse enteric coating to ensure that the capsule dissolves in the stomach environment, rather than before, so that the gastroretentive system unfolds and assumes an open configuration inside the stomach as intended.

[0006] Similarly, the methods of preparing a gastroretentive dosage form provided herein may include constraining the folded gastroretentive system with a sheath and encapsulating the constrained gastroretentive system with a capsule. In some embodiments, the methods of preparing a gastroretentive dosage form may also include coating the encapsulated gastroretentive system with a reverse enteric coating to ensure dissolution of the capsule and delivery of the gastroretentive system in the patient's stomach.

[0007] In some embodiments, a gastroretentive dosage form is provided that comprises a gastroretentive system in a folded configuration, a capsule that encapsulates the gastroretentive system in the folded configuration, and a coating on the capsule, the gastroretentive dosage form configured to release the gastroretentive system in a patient's stomach and cause the gastroretentive system to assume an open configuration.

[0008] In some embodiments of the gastric retention dosage form, the gastric retention dosage form causes the gastric retention system to assume the open configuration within a first time upon exposure to an aqueous pH 7.0 environment, which first time is longer than a second time for an uncoated gastric retention dosage form comprising an uncoated capsule that causes the gastric retention system to assume the open configuration upon exposure to an aqueous pH 7.0 environment.

[0009] In some embodiments of the gastroretentive dosage form, the first time period is at least 1 minute longer than the second time period.

[0010] In some embodiments of the gastroretentive dosage form, the gastroretentive dosage form causes the gastroretentive system to adopt the open configuration within at least 20 minutes upon exposure to the aqueous pH 7.0 environment.

[0011] In some embodiments of the gastroretentive dosage form, the gastroretentive dosage form causes the gastroretentive system to adopt the open configuration within at least 30 minutes upon exposure to the aqueous pH 7.0 environment.

[0012] In some embodiments of the gastric retention dosage form, the gastric retention dosage form causes the gastric retention system to assume the open configuration within a third time upon exposure to an aqueous pH 3.0 environment, which third time is longer than a fourth time for an uncoated gastric retention dosage form comprising an uncoated capsule, at which the uncoated gastric retention dosage form causes the gastric retention system to assume the open configuration upon exposure to an aqueous pH 3.0 environment.

[0013] In some embodiments of the gastroretentive dosage form, the third time period is at least 15 seconds longer than the fourth time period.

[0014] In some embodiments of the gastroretentive dosage form, the gastroretentive dosage form causes the gastroretentive system to adopt the open configuration in less than 30 minutes upon exposure to the aqueous pH 3.0 environment.

[0015] In some embodiments of the gastroretentive dosage form, the gastroretentive dosage form causes the gastroretentive system to adopt the open configuration in less than 15 minutes upon exposure to the aqueous pH 3.0 environment.

[0016] In some embodiments of the gastroretentive dosage form, the gastroretentive dosage form comprises a sheath, the sheath surrounding at least a portion of the gastroretentive system in the folded configuration.

[0017] In some embodiments of the gastroretentive dosage form, the coating comprises a reverse enteric polymer.

[0018] In some embodiments of the gastroretentive dosage form, the reverse enteric polymer comprises a polymethacrylate-based polymer.

[0019] In some embodiments of the gastroretentive dosage form, the coating comprises an anti-adherent agent.

[0020] In some embodiments of the gastroretentive dosage form, the anti-adherent agent comprises at least one of talc or magnesium stearate.

[0021] In some embodiments of the gastroretentive dosage form, the coating comprises a plasticizer.

[0022] In some embodiments of the gastroretentive dosage form, the plasticizer comprises at least one of a phthalate, phosphate, citrate, tartrate, adipate, sebacate, sulfonamide, succinate, glycolate, glycerolate, benzoate, myristate, polyethylene glycol, phenyl halide, or poloxamer.

[0023] In some embodiments of the gastroretentive dosage form, the plasticizer comprises at least one of triacetin or dibutyl sebacate.

[0024] In some embodiments of the gastroretentive dosage form, the coating includes a hydration aid.

[0025] In some embodiments of the gastroretentive dosage form, the hydration aid comprises at least one of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, mannitol, or hydroxypropyl methylcellulose.

[0026] In some embodiments of the gastroretentive dosage form, the coating comprises 50-95% by weight of a reverse enteric polymer.

[0027] In some embodiments of the gastroretentive dosage form, the coating comprises 3-25% by weight of an anti-adherent agent.

[0028] In some embodiments of the gastroretentive dosage form, the coating comprises 1-20% by weight of a plasticizer.

[0029] In some embodiments of the gastroretentive dosage form, the coating comprises 3-35% by weight of a hydration aid.

[0030] In some embodiments of the gastroretentive dosage form, the sheath comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

[0031] In some embodiments of the gastroretentive dosage form, the capsule comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

[0032] In some embodiments of the gastroretentive dosage form, the gastroretentive dosage form is used to treat a patient.

[0033] In some embodiments of this gastroretentive dosage form, the patient is a human.

[0034] In some embodiments, a coating for an encapsulated gastroretentive system is provided, the coating comprising 50-95% by weight of a reverse enteric polymer, 3-25% by weight of an anti-adherent agent, and 1-20% by weight of a plasticizer.

[0035] In some embodiments of the coating, the coating is on a surface of the capsule to form a coated capsule.

[0036] In some embodiments of the coating, the coated capsule encapsulates a gastroretentive system to form a gastroretentive dosage form that is configured to release the gastroretentive system in the patient's stomach and cause the gastroretentive system to assume an open configuration.

[0037] In some embodiments of the coating, the coating comprises 5-35% by weight of a hydration aid.

[0038] In some embodiments of the coating, the hydration aid comprises at least one of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, mannitol, or hydroxypropyl methylcellulose.

[0039] In some embodiments of the coating, the reverse enteric polymer comprises a polymethacrylate-based polymer.

[0040] In some embodiments of the coating, the anti-adherent agent comprises at least one of talc or magnesium stearate.

[0041] In some embodiments of the coating, the plasticizer comprises a phthalate, phosphate, citrate, tartrate, adipate, sebacate, sulfonamide, succinate, glycolate, glycerolate, benzoate, myristate, polyethylene glycol, phenyl halide, or poloxamer.

[0042] In some embodiments of the coating, the plasticizer comprises at least one of triacetin and dibutyl sebacate.

[0043] In some embodiments of the coating, the coating is soluble in an aqueous solution.

[0044] In some embodiments of the coating, the coating is soluble in organic solvents.

[0045] In some embodiments of the coating, the gastroretentive dosage form causes the gastroretentive system to assume the open configuration within a first time upon exposure to an aqueous pH 7.0 environment, which first time is longer than a second time for an uncoated gastroretentive dosage form comprising an uncoated capsule that causes the gastroretentive system to assume the open configuration upon exposure to an aqueous pH 7.0 environment.

[0046] In some embodiments of this coating, the first time period is at least 1 minute longer than the second time period.

[0047] In some embodiments of the coating, the gastroretentive dosage form causes the gastroretentive system to assume the open configuration within at least 20 minutes upon exposure to the aqueous pH 7.0 environment.

[0048] In some embodiments of the coating, the gastroretentive dosage form causes the gastroretentive system to assume the open configuration within at least 30 minutes upon exposure to the aqueous pH 7.0 environment.

[0049] In some embodiments of the coating, the gastroretentive dosage form causes the gastroretentive system to assume the open configuration within a third time upon exposure to an aqueous pH 3.0 environment, which third time is longer than a fourth time for an uncoated gastroretentive dosage form comprising an uncoated capsule, at which the uncoated gastroretentive dosage form causes the gastroretentive system to assume the open configuration upon exposure to an aqueous pH 3.0 environment.

[0050] In some embodiments of this coating, the third period of time is at least 15 seconds longer than the fourth period of time.

[0051] In some embodiments of the coating, the gastroretentive dosage form causes the gastroretentive system to assume the open configuration in less than 30 minutes upon exposure to the aqueous pH 3.0 environment.

[0052] In some embodiments of the coating, the gastroretentive dosage form causes the gastroretentive system to assume the open configuration in less than 15 minutes upon exposure to the aqueous pH 3.0 environment.

[0053] In some embodiments, a gastroretentive dosage form is provided, the gastroretentive dosage form comprising a coating according to one or more embodiments provided herein, the gastroretentive dosage form being used to treat a patient.

[0054] In some embodiments of this gastroretentive dosage form, the patient is a human.

[0055] In some embodiments, a method for producing a gastroretentive dosage form is provided, the method comprising encapsulating the gastroretentive system in a folded form with a capsule and coating the capsule with a reverse enteric coating to form the gastroretentive dosage form.

[0056] In some embodiments of this method, the method includes constraining the gastroretentive system in the folded form with a sheath prior to encapsulation.

[0057] In some embodiments of this method, coating the capsule with a reverse enteric coating comprises pan-coating the capsule.

[0058] In some embodiments of this method, the reverse enteric coating comprises a reverse enteric polymer, an anti-tack agent, and a plasticizer.

[0059] In some embodiments of this method, the anti-adherent agent comprises at least one of talc or magnesium stearate.

[0060] In some embodiments of this method, the plasticizer comprises at least one of a phthalate, phosphate, citrate, tartrate, adipate, sebacate, sulfonamide, succinate, glycolate, glycerolate, benzoate, myristate, polyethylene glycol, phenyl halide, or poloxamer.

[0061] In some embodiments of this method, the plasticizer comprises at least one of triacetin or dibutyl sebacate.

[0062] In some embodiments of this method, the reverse enteric coating includes a hydration aid.

[0063] In some embodiments of this method, the hydration aid comprises at least one of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, mannitol, or hydroxypropyl methylcellulose.

[0064] In some embodiments of this method, the capsule comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

[0065] In some embodiments of this method, the sheath comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

[0066] In some embodiments of this method, the gastroretentive dosage form is configured to release the gastroretentive system in the patient's stomach, causing the gastroretentive system to assume an open configuration.

[0067] In some embodiments of this method, the gastroretentive dosage form causes the gastroretentive system to assume the open configuration within a first time upon exposure to an aqueous pH 7.0 environment, and the first time is longer than a second time for an uncoated gastroretentive dosage form comprising an uncoated capsule that causes the gastroretentive system to assume the open configuration upon exposure to the aqueous pH 7.0 environment.

[0068] In some embodiments of this method, the first period of time is at least 1 minute longer than the second period of time.

[0069] In some embodiments of this method, the gastroretentive dosage form causes the gastroretentive system to adopt the open configuration within at least 20 minutes upon exposure to the aqueous pH 7.0 environment.

[0070] In some embodiments of this method, the gastroretentive dosage form causes the gastroretentive system to adopt the open configuration within at least 30 minutes upon exposure to the aqueous pH 7.0 environment.

[0071] In some embodiments of this method, the gastroretentive dosage form causes the gastroretentive system to assume the open configuration within a third time upon exposure to an aqueous pH 3.0 environment, which third time is longer than a fourth time for an uncoated gastroretentive dosage form comprising an uncoated capsule, at which the uncoated gastroretentive dosage form causes the gastroretentive system to assume the open configuration upon exposure to an aqueous pH 3.0 environment.

[0072] In some embodiments of this method, the third period of time is at least 15 seconds longer than the fourth period of time.

[0073] In some embodiments of this method, the gastroretentive dosage form causes the gastroretentive system to assume the open configuration in less than 30 minutes upon exposure to the aqueous pH 3.0 environment.

[0074] In some embodiments of this method, the gastroretentive dosage form causes the gastroretentive system to assume the open configuration in less than 15 minutes upon exposure to the aqueous pH 3.0 environment.

[0075] In some embodiments, a gastroretentive dosage form is made using the method of any of the embodiments provided herein, and the gastroretentive dosage form is used to treat a patient.

[0076] In some embodiments of this gastroretentive dosage form, the patient is a human.

[0077] In some embodiments, a coated dosage form is provided, the coated dosage form comprising a dosage form and a coating comprising a reverse enteric polymer coating the dosage form;

[0078]

number

[0079] It is.

[0080] In some embodiments of the coated dosage form, the coating comprises magnesium stearate.

[0081] In some embodiments of the coated dosage form, the dosage form comprises one of a tablet, a capsule, or a coated gastroretentive system.

[0082] In some embodiments of the coated dosage form, the dosage form comprises a capsule.

[0083] In some embodiments of the coated dosage form, the capsule encapsulates a gastroretentive system.

[0084] In some embodiments of the coated dosage form, the static coefficient of friction of the coated dosage form is less than 0.3.

[0085] In some embodiments of the coated dosage form, the static coefficient of friction of the coated dosage form is less than 0.2.

[0086] In some embodiments of the coated dosage form, the static coefficient of friction of the coated dosage form is less than 0.1.

[0087] In some embodiments of this coated dosage form,

[0088]

number

[0089] It is.

[0090] In some embodiments of the coated dosage form, the static coefficient of friction is at least 0.08 less than the static coefficient of friction of the uncoated dosage form.

[0091] In some embodiments of the coated dosage form, the static coefficient of friction of the coated dosage form is at least 0.15 less than the static coefficient of friction of the uncoated dosage form.

[0092] In some embodiments of the coated dosage form, the static coefficient of friction of the coated dosage form is at least 0.2 less than the static coefficient of friction of the uncoated dosage form.

[0093] In some embodiments of the coated dosage form, the reverse enteric polymer comprises a polymethacrylate.

[0094] In some embodiments of the coated dosage form, the coating comprises 10-50% by weight of a reverse enteric polymer.

[0095] In some embodiments of the coated dosage form, the coating comprises an anti-adherent agent.

[0096] In some embodiments of the coated dosage form, the anti-adherent agent comprises talc.

[0097] In some embodiments of the coated dosage form, the coating comprises 5-30% by weight of an anti-adherent agent. [Brief description of the drawings]

[0098] [Figure 1A-B] 1A and 1B show a gastroretention system in an open configuration, according to some embodiments. [Figure 1C]FIG. 1C illustrates a gastroretentive system in an open configuration, according to some embodiments. [Diagram 2] FIG. 2 shows a gastroretention system in a folded configuration, according to some embodiments. [Figure 3A-D] Figure 3A shows a folded gastric retention system and sheath according to some embodiments, Figure 3B shows a gastric retention system with a sheath according to some embodiments, Figure 3C shows a gastric retention system with a sheath and a two-piece capsule body according to some embodiments, and Figure 3D shows a gastric retention system with a sheath disposed within a two-piece capsule body and a two-piece capsule cap according to some embodiments. [Figure 4A-D] Figure 4A shows a folded gastric retention system and sheath according to some embodiments, Figure 4B shows a gastric retention system with a sheath according to some embodiments, Figure 4C shows a gastric retention system with a sheath and a two-piece capsule body according to some embodiments, and Figure 4D shows a gastric retention system with a sheath disposed within a two-piece capsule body and a two-piece capsule cap according to some embodiments. [Figure 5A-C] Figure 5A shows a folded gastric retention system with a sheath on the core side according to some embodiments, Figure 5B shows a folded gastric retention system with an encapsulated sheath according to some embodiments, and Figure 5C shows a folded gastric retention system with an encapsulated sheath according to some embodiments. [Figure 6A-D] Figure 6A shows a folded gastric retention system according to some embodiments, Figure 6B shows a sheathed gastric retention system according to some embodiments, Figure 6C shows an encapsulated gastric retention system according to some embodiments, and Figure 6D shows a coated encapsulated gastric retention system according to some embodiments. [Figure 7] FIG. 7 illustrates a method for producing a gastroretentive dosage form according to some embodiments. [Figure 8A-D]Figure 8A shows a sheathed compressed / folded gastric retention system including filaments according to some embodiments, Figure 8B shows a sheathed compressed / folded gastric retention system including filaments according to some embodiments, Figure 8C shows a sheathed compressed / folded gastric retention system including filaments according to some embodiments, Figure 8D shows a sheathed compressed / folded gastric retention system including filaments according to some embodiments. [Fig. 8E-G] Figure 8E shows a compressed / folded gastric retention system including a filament, sheathed arms, and encapsulated in a two-piece capsule according to some embodiments. Figure 8F shows a compressed / folded gastric retention system including a filament, sheathed arms, and encapsulated in a two-piece capsule according to some embodiments. Figure 8G shows an encapsulated compressed / folded gastric retention system according to some embodiments. [Figure 9] FIG. 9 shows static coefficient of friction data for various coating formulations, according to some embodiments. [Figure 10A] FIG. 10A shows data on gastric retention dosage form expansion time at various coating weights, according to some embodiments. [Figure 10B] FIG. 10B shows data on gastric retention dosage form expansion time at various coating weights, according to some embodiments. [Figure 11] FIG. 11 shows data comparing coated and uncoated gastroretentive dosage forms according to some embodiments. [Figure 12] FIG. 12 shows the uncoated development times for the two coating formulations. [Figure 13] FIG. 13 shows the development times at both pH 3 and pH 7 for the two coating formulations also depicted in FIG. [Figure 14A]FIG. 14A shows an Instron test tool used to test deployment time, according to some embodiments. [Figure 14B-C] 14B shows a diagram of a custom sled for testing static coefficient of friction, according to some embodiments, and FIG. 14C shows a diagram of a custom sled for testing static coefficient of friction, according to some embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0099] Described herein are capsules and capsule coatings for gastroretentive systems. Also provided are methods for preparing gastroretentive dosage forms using the capsules and capsule coatings provided herein. As described above, the gastroretentive system is designed to be administered to a patient in a folded or collapsed form (i.e., allowing the drug delivery device to be swallowed and easily passed to the patient's stomach). Once the gastroretentive system enters the patient's stomach, it unfolds to an open form. When the gastroretentive system is physically unfolded or unfolded, the dosage form is in an effective size (i.e., the gastroretentive system in an open form) that is too large to pass through the patient's pyloric valve (the opening between the stomach and the large intestine). The deployed or expanded gastroretentive system can remain in the patient's stomach for a predetermined period of time (e.g., 24 hours, 48 ​​hours, 7 days, 10 days, etc.).

[0100] A particular challenge of gastroretentive systems, however, is controlling the opening / unfolding of the gastroretentive system. A gastroretentive system that unfolds too early (e.g., in the patient's esophagus) or too late (e.g., in the patient's intestine) is undesirable. A gastroretentive system that cannot unfold at all may pass entirely through the patient's gastrointestinal tract in a collapsed configuration. In each of these hypothetical situations, the gastroretentive system would be unable to properly deliver a therapeutic agent (e.g., an active pharmaceutical ingredient) to the patient's stomach.

[0101] Thus, the capsules and capsule coatings provided herein are designed to provide good control over the placement of the gastroretentive system to effectively deliver the therapeutic agent to the patient's stomach. In particular, the gastroretentive dosage form comprising the capsule and / or capsule coating according to the embodiments provided herein is likely to deploy and assume an open configuration within the patient's body at a desired location for a desired time. For example, the gastroretentive dosage form may be used to deliver a therapeutic agent to the patient's stomach. Thus, the particular capsule and / or capsule coating used to prepare the gastroretentive dosage form may be specially formulated to ensure that the gastroretentive system does not deploy too early (e.g., in the patient's esophagus), too late (e.g., in the patient's intestine), or does not deploy at all.

[0102] As used herein, a "gastric retention system" refers to a dosage form containing a therapeutic agent and configured to be administered to a patient in a folded configuration. A "gastric retention dosage form" or a "coated gastric retention dosage form" includes a folded gastric retention system and is configured to maintain the gastric retention system in the folded configuration until deployment. A gastric retention dosage form may include a capsule and / or capsule coating according to embodiments described herein. Additionally, "unfolding time" is defined as the time it takes for a gastric retention system to assume an open configuration.

[0103] In some embodiments, the capsule may include a sheath or band configured to hold the gastroretentive system in a folded configuration. The capsule may encapsulate the gastroretentive system folded and held in the folded configuration by the sheath or band.

[0104] In some embodiments, the encapsulated gastroretentive system may be coated with a capsule coating formulated to control the release of the gastroretentive system. For example, the encapsulated gastroretentive system may be coated with a reverse-enteric coating. The reverse-enteric coating may facilitate dissolution of the capsule in the patient's stomach and ensure that the capsule and capsule coating dissolve in the stomach so that the gastroretentive system can be released to an open configuration. The reverse-enteric coating may also prevent the capsule from dissolving in the patient's esophagus and / or intestines, preventing premature and / or delayed release of the gastroretentive system. In some embodiments, the coating may include a polymer. In some embodiments, the coating may include a plasticizer. In some embodiments, the coating may include an anti-adherent agent. In some embodiments, the coating may include a hydrating agent.

[0105] The general principles of gastroretentive systems and capsules and capsule coatings capable of controlling the release of gastroretentive systems are described below.

[0106] General principles of the gastroretentive system A description of the gastroretention system and a method of operation for delivering a therapeutic agent to a patient is provided below. In particular, the following discussion includes how the gastroretention system is designed to deliver a therapeutic agent to a patient over an extended period of time, how the gastroretention system is designed for administration, how the gastroretention system is designed to deploy in the patient's stomach and deliver a therapeutic agent to the patient's stomach, how the therapeutic agent of the gastroretention system elutes from the device to deliver the therapeutic agent to the patient, how the gastroretention system passes through the stomach, and how the gastroretention system is designed to account for several specific safety measures.

[0107] A gastric retention dosage form can be designed to be delivered to a patient's stomach by swallowing, by a feeding tube, by a stomach tube, or by other methods. Once the gastric retention dosage form is properly positioned in the stomach, it can be retained in the stomach for a desired retention time (e.g., 3 days, 7 days, 2 weeks, etc.). Once properly positioned in the stomach, a gastric retention dosage form resists passage through the pyloric valve that separates the stomach from the small intestine. The gastric retention dosage form can release a therapeutic agent (i.e., API or drug) in a controlled amount over the retention time. While retained in the stomach, the dosage form should not impede the normal passage of food or other stomach contents. Once the desired retention time has elapsed, the dosage form can be emptied from the stomach (i.e., passed through the pyloric valve) and easily eliminated from the patient.

[0108] To administer the gastric retention system to a patient, the gastric retention system may be folded into a shape small enough to be swallowed or otherwise administered. In some embodiments, the folded gastric retention system is held in a capsule or other container that can be swallowed by the patient. In some cases, the gastric retention system may be delivered to the patient via a gastrostomy tube, a feeding tube, a gastric tube, or other route of administration to the stomach. Further details regarding examples of folding and encapsulating a gastric retention system are provided below.

[0109] 1A-1C provide examples of collapsible or compressible gastroretention systems. Specifically, the collapsible or compressible gastroretention systems shown in Figures 1A-1C are provided in an unfolded configuration.

[0110] For example, the annular design gastric retention system 100 shown in FIG. 1A can be twisted into a double helix. In particular, the gastric retention system 100 includes a carrier polymer-drug member 102 and a linking portion 104. In some embodiments, the linking portion 104 can include a linking polymer. In some embodiments, the gastric retention system 100 can be folded or helically twisted at one or more linking polymer joints 104 to be packed into a capsule in a folded configuration. Once the capsule dissolves in the stomach, the gastric retention system 100 unfolds into a circular, open, or unfolded configuration, preventing passage through the pyloric valve.

[0111] As shown in FIG. 1B, gastric retention system 100 may also be star-shaped (star-like) according to some embodiments. In some embodiments, star-shaped gastric retention system 100 is constructed around a central elastomer 106. Central elastomer 106 may include one or more elongated members 108 or "arms" extending radially from it. The arms may be formed by carrier polymer-drug member 102 and linkages 104 that include a linking polymer. One or more polymer-drug members 102 and linkages 104 together make up the "arms" of this "star" configuration. The presence of elastomer 106 allows gastric retention system 100 to be folded for packing into a capsule.

[0112] 1C illustrates a gastric retention system 100 including three "arms" according to some embodiments. This configuration may also include a central elastomer 106 from which the three "arms" radiate. Each of the three arms further includes a polymer-drug member 102 and a linkage 104.

[0113] 2 illustrates a folded gastroretentive system 200 according to some embodiments. As shown, the device can be folded at the central elastomer 206, bringing the ends of each "arm" together. This figure also illustrates how the carrier polymer-medicine member 102 and linkages 104 of each arm can be oriented in the folded configuration.

[0114] The gastroretentive system 100 in its folded configuration may be restrained (i.e., held in its folded configuration) by a sheath or band. In some embodiments, the gastroretentive system in its folded configuration (with or without a sheath or band) may be encapsulated in a capsule to form a gastroretentive dosage form. In some embodiments, the gastroretentive dosage form may be coated with a reverse enteric coating to ensure deployment of the gastroretentive system in the patient's stomach.

[0115] Once the gastroretentive dosage form reaches the patient's stomach, the capsule and / or capsule coating of the gastroretentive dosage form can dissolve / open to release the folded gastroretentive system. Once released, the gastroretentive system unfolds to assume an open configuration, such as a ring or star shape as provided in Figures 1A-1C. The dimensions of the opened gastroretentive system are suitable to prevent the device from passing through the pyloric valve for the period of time the device is to remain in the stomach. In some embodiments, the folded gastroretentive system may also be secured by a dissolvable retention band or sheath that can prevent premature unfolding of the gastroretentive system in the event of capsule breakage.

[0116] While in the stomach, the gastroretentive system is compatible with digestion and other normal functions of the stomach or gastrointestinal tract. The gastroretentive system does not impede or impede the passage of chyme (partially digested food) or other stomach contents from the stomach through the pyloric valve to the duodenum.

[0117] Once released from the capsule into the stomach, the therapeutic agent of the gastroretentive system begins to take effect. In some embodiments, the gastroretentive system includes a plurality of carrier polymer-drug members. The carrier polymer-drug members may include a carrier polymer, a dispersing agent, and a therapeutic agent (or a salt thereof). The plurality of carrier polymer-drug members are linked together by one or more linking polymer members. The therapeutic agent is allowed to dissolve from the carrier polymer-drug members into the gastric fluids of the patient for the desired retention period of the system. The amount of release of the therapeutic agent is controlled by proper formulation of the carrier polymer-drug member, including the use of a dispersing agent in the carrier polymer-drug member formulation and grinding the therapeutic agent to particles of the desired size before mixing the therapeutic agent with the carrier polymer and dispersing agent.

[0118] In some embodiments, the gastric retention system may include a filament (or "webbing") between the arms of the gastric retention system. A gastric retention system with a filament may help improve the gastric retention of the gastric retention system. In particular, the use of a filament may help to make the gastric retention time more consistent and / or longer. Thus, a gastric retention system including a filament may make the gastric retention time more predictable and / or more controllable. A gastric retention system with a predictable and / or controllable gastric retention time may minimize the possibility that the gastric retention system will pass through the stomach and deploy late in the gastrointestinal tract (i.e., intestines) or pass through the gastrointestinal tract without deploying at all. In each of these possible scenarios, the therapeutic agent of the gastric retention dosage form will not be delivered to the patient as intended.

[0119] In some embodiments, a filament wrapped circumferentially around the gastric retention system and connecting the arms of the gastric retention system can help, for example, to prevent premature passage through the pylorus of the patient's stomach.

[0120] Additionally, a coating may be applied to the exterior surface of the gastroretentive system, which may include additional therapeutic agents or agents that may affect the release of the therapeutic agent or the residence time of the gastroretentive system.

[0121] Once the desired retention time has elapsed, the gastric retention system is emptied from the stomach. To do so, various components of the gastric retention system are designed to weaken or degrade. The particular dimensions of the system are also taken into consideration. In the native, open configuration, the gastric retention system is designed to resist passage through the pyloric valve. The linked polymeric components of the gastric retention system, however, are selected to gradually degrade during the particular retention time in the stomach. Once the linked polymeric components have been sufficiently weakened by degradation, the gastric retention system will lose a critical resistance and compress or reduce in size and may break down into smaller pieces. Any reduced size dosage forms and smaller pieces are designed to pass through the pyloric valve. The system then passes through the intestine and is emptied from the patient. In some embodiments, the gastric retention system may be made from a soft material such that once the retention time has elapsed, the gastric retention system can pass through the pyloric valve intact without having to break down into many small pieces.

[0122] There are several safety considerations to account for when designing and administering gastric retention systems and gastric retention dosage forms. Of particular importance is that the gastric retention system remain in a folded configuration until the stomach is reached. If the gastric retention system were to open or unfold before reaching the patient's stomach, the patient would run the risk of esophageal obstruction. Similarly, if the complete gastric retention dosage form does not unfold and the gastric retention system does not expand to an open configuration before passing through the pyloric valve, it would risk doing so in the patient's intestine and causing an intestinal obstruction. Therefore, the capsules and capsule coatings according to the embodiments described herein are designed to control the unfolding of the gastric retention system to improve patient safety.

[0123] Examples of gastroretentive systems can be found in International Application No. PCT / US2018 / 051816, International Publication No. WO 2015 / 191920, International Publication No. WO 2017 / 070612, International Publication No. WO 2017 / 100367, International Publication No. WO 2018 / 064630, International Publication No. WO 2017 / 205844, International Publication No. WO 2018 / 227147, and U.S. Patent Application No. 62 / 933,211, each of which is incorporated herein by reference in its entirety.

[0124] Capsules for gastroretentive systems The following describes capsules for gastroretentive systems, including both sheaths (or bands) and capsules (such as hard shell capsules). In particular, the sheaths / bands described below may be used to hold the gastroretentive system in a folded configuration. Capsules may be used to encapsulate the gastroretentive system (with or without a sheath) and control when the gastroretentive system is released in the patient's stomach.

[0125] A capsule has been developed according to embodiments provided herein to enhance the performance of the gastroretentive system. Specifically, the capsule has been developed to maintain the gastroretentive system in a folded configuration between the time of administration and the time of reaching the stomach. Once the gastroretentive dosage form reaches the stomach, the capsule is configured to rapidly open and / or dissolve. A rapidly opening or rapidly dissolving capsule can be used to ensure that the gastroretentive system is released inside the stomach before passing through the pyloric valve.

[0126] A sheath that mechanically holds the gastric device in a folded configuration In some embodiments, the gastroretentive dosage forms described herein may include a "sheath" or "band." The sheath or band may restrain the gastroretentive system in a folded configuration. When used with a capsule, the sheath may reduce the outward pressure on the capsule. This may reduce any risk of the capsule breaking and premature deployment of the gastroretentive system. The sheath further provides a second retention layer (when used with a capsule) and also reduces the possibility of the dosage form losing its ability to remain folded, thereby prematurely disintegrating upon administration but before placement in the stomach. Thus, in the event of capsule failure, the sheath provides a second layer of protection from premature deployment of the gastroretentive system.

[0127] 3B illustrates a compressed / folded gastric retention system 310 constrained by a sheath 312 according to some embodiments. As shown, the gastric retention system 310 in the folded configuration is capped by the sheath 312 at the arm ends.

[0128] Figure 4B shows a compressed / folded gastric retention system 410 constrained by a sheath 412 according to some embodiments. Unlike the sheath 312 of Figure 3B, the sheath 412 of Figure 4B includes two open ends. Thus, the compressed / folded gastric retention system 410 passes through the sheath 412 such that the gastric retention system 410 is exposed at both open ends of the sheath 412. Similar to that of Figure 3B, the gastric retention system 410 is constrained by the sheath 412 at the arm ends of the gastric retention system 410.

[0129] In some embodiments, the sheath may be gelatin-based. In some embodiments, the sheath may be hydroxypropylmethylcellulose (HPMC)-based or pullulan-based. Other suitable materials (e.g., carrageenan, starch, cellulose, etc.) may also be included in the sheath. Suitable sheaths may be, for example, VCaps® HPMC, VCaps® Plus HPMC, Plantcaps®, or ConiSnap®.

[0130] In some embodiments, the size and / or thickness of the sheath may be optimized to control the deployment time of the gastroretentive system. For example, a sheath with a thin shell thickness may be used to release the gastroretentive system quickly. In some embodiments, a sheath with a thick shell thickness may be used to release the gastroretentive system slowly. In some embodiments, a sheath with a short length and / or width may be used to control the release of the gastroretentive system from the gastroretentive dosage form. In some embodiments, a sheath with a large length and / or width may be used to control the release of the gastroretentive system from the gastroretentive dosage form. Using a sheath with a large length / width may, for example, help to delay the release of the gastroretentive system. In some embodiments, a sheath with a small length / width may be used to speed up the release of the gastroretentive system. In some embodiments, the placement of the sheath on the folded gastroretentive system may also be optimized to control the deployment time. The position of the sheath may be optimized, for example, with respect to the folding force and / or with respect to the body position and / or the capsule cap.

[0131] Some embodiments may further include a wicking agent between the sheath and the folded gastroretentive system. The use of a wicking agent may facilitate rapid deployment of the gastroretentive system. In some embodiments, the wicking agent may include a hydrophilic polymer, a hygroscopic polymer, a hygroscopic wetting agent, and / or a water retention agent. Examples of polymers include polysaccharide-based polymers such as hydroxypropylmethylcellulose, carboxymethylcellulose, starch, pectin, chitosan, alginates, other natural or semi-synthetic polymers such as gelatin, collagen, silk fibroin, and / or non-cellulosic synthetic polymers such as polyethylene glycol, polyethyl glycol-polypropylene glycol di- and tri-block copolymers, polyvinylpyrrolidone, and derivatives thereof. Non-polymeric wicking agents may include wetting agents and water retention materials including sugars such as polysorbates, glycerol, propanediol, sucrose, glucose, dextrose, mannitol, maltitol, mannose, and various salts.

[0132] Capsule for encapsulating a gastroretentive system In addition to the "sheath" or "band" described above and provided in Figures 2 and 3, a capsule may also be used to hold the gastroretentive system in a folded configuration until the dosage form reaches the stomach. A capsule may be used in addition to or instead of a sheath.

[0133] The capsules may exhibit various advantages including protection, blinding capabilities, and good coating adhesion. For example, the capsules provide resistance to physical impacts and external environmental factors (such as humidity). This protective layer can improve the shelf life of the gastroretentive dosage form and provide protection during transportation. The capsules are also opaque to allow for blinding (i.e., for use in clinical trials). The capsules further provide a suitable surface for capsule coating (discussed in more detail below). The capsule coating according to the embodiments described herein adheres well to the capsule surface.

[0134] As mentioned above, the capsule and / or sheath according to the embodiments provided herein are designed to protect the patient from expansion in the esophagus. The expansion time of the capsule and / or sheath in a pH 7.0 environment (i.e., about the pH of the esophagus) may be, for example, 5 to 180 minutes, 20 to 120 minutes, or 20 to 60 minutes. In some embodiments, the expansion time of the capsule and / or sheath in an aqueous pH 7.0 environment may be less than 180 minutes, less than 160 minutes, less than 140 minutes, less than 120 minutes, less than 100 minutes, less than 80 minutes, less than 60 minutes, less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 25 minutes, or less than 20 minutes. In some embodiments, the deployment time of the capsule and / or sheath in an aqueous pH 7.0 environment may be greater than 15 minutes, greater than 20 minutes, greater than 25 minutes, greater than 30 minutes, greater than 40 minutes, greater than 50 minutes, greater than 60 minutes, greater than 80 minutes, greater than 100 minutes, greater than 120 minutes, greater than 140 minutes, or greater than 160 minutes.

[0135] The capsules and / or sheaths according to the embodiments provided herein can also be designed to dissolve and / or open rapidly in the stomach environment. As mentioned above, once the gastric retention dosage form reaches the stomach, it should dissolve and / or open rapidly to release and deploy the gastric retention system in the stomach. If the capsules and / or sheaths fail to dissolve / open quickly, there is a risk that the gastric retention dosage form will pass through the pyloric valve before releasing the gastric retention system. Therefore, the capsules and / or sheaths according to the embodiments provided herein are designed to dissolve / open quickly and consistently. In some embodiments, the dissolution / opening of the capsules and / or sheaths is less or not reliable at low pH.

[0136] Moreover, encapsulation of the gastroretention system according to the embodiments provided herein allows for a smooth, non-sticky surface for ease of swallowing (preventing esophageal retention), and allows for non-greasy, flawless processing, storage and transportation steps.

[0137] In some embodiments, the capsule may be gelatin-based. In some embodiments, the capsule and / or sheath may be hydroxypropylmethylcellulose (HPMC)-based or pullulan-based. Other suitable materials (such as carrageenan, starch, cellulose, etc.) may also be included in the capsule and / or sheath. Suitable capsules may include VCaps® HPMC, VCaps® Plus HPMC, Plantcaps®, or Coni-Snap®.

[0138] In some embodiments, in addition to the coatings detailed below, the size and / or thickness of the capsule may be optimized to control the deployment time of the gastroretentive system. For example, a capsule with a thin shell thickness may be used to release the gastroretentive system quickly. In some embodiments, a capsule with a thick shell thickness may be used to release the gastroretentive system slowly. In some embodiments, a capsule with a small length and / or width may be used to control the release of the gastroretentive system from the gastroretentive dosage form. In some embodiments, a capsule with a large length and / or width may be used to control the release of the gastroretentive system from the gastroretentive dosage form. For example, using a capsule with a large length / width can help to delay the release of the gastroretentive system. In some embodiments, a capsule with a small length / width may be used to speed up the release of the gastroretentive system.

[0139] The folded gastroretention system (restrained by a sheath or not) may be inserted into the two-piece capsule using any suitable encapsulation technique. The gastroretention system may be, for example, folded and encapsulated manually. In some embodiments, the sheath may be a size 0 or 0EL capsule cap. Once restrained by the sheath, the gastroretention system may be encapsulated with the sheathed end of the gastroretention system inside the body of the two-piece capsule. If a 0 or 0EL capsule cap is used to sheath the gastroretention system, for example, a slightly larger capsule (e.g., size 00EL capsule) may be used to encapsulate the sheathed gastroretention system. In some embodiments, the folded gastroretention system may be encapsulated without the use of a sheath.

[0140] 3A-3D and 4A-4D show the steps of encapsulation according to some embodiments. The sheath 312 in Figs. 3A-3D is a complete cap that fits over one end of the folded gastroretention system 310. The sheath 412 in Figs. 4A-4D is cylindrical in shape with an open top and bottom. Fig. 3A specifically shows the gastroretention system 310 folded with the sheath 312. Fig. 3B shows the sheath 312 restraining the gastroretention system 310 in the folded configuration. Fig. 3C shows the gastroretention system 310 including the sheath 312 inserted into a two-piece capsule body 314. Fig. 3D shows the sheath 312 and the body 314 including the gastroretention system capped with a two-piece capsule cap 316.

[0141] Similarly, Figure 4A shows gastric retention system 410 folded with a sheath 412. Figure 4B shows the sheath 412 restraining gastric retention system 410 in a folded configuration. Figure 4C shows gastric retention system 410 including sheath 412 inserted into a two-piece capsule body 414. Figure 4D shows body 414 including sheathed gastric retention system 410 capped with a two-piece capsule cap 416.

[0142] The configuration of the sheath and / or two-piece capsule may vary depending on the gastroretentive dosage form as well. In some embodiments, the placement of the sheath and / or two-piece capsule relative to the core side and arm side of the gastroretentive system may affect the deployment time of the gastroretentive system.

[0143] 5A-5C show a few different configurations for the sheath and two-piece capsule arrangement. Specifically, FIG. 5A shows a compressed / folded gastric retention system 510A. As shown, the gastric retention system 510A can be sheathed by a capsule sheath 512A. FIG. 5A shows the gastric retention system 510A sheathed on the core side of the folded gastric retention system 510A. The gastric retention system 510A may, however, be sheathed on the arm side in some embodiments. In this view, the core side of the gastric retention system 510A is shaded. The opposite side of the compressed / folded gastric retention system 510A is the arm side, where the arms come together when the gastric retention system is folded. Once the sheath 512A is placed over the compressed / folded gastric retention system 510A, a sheathed compressed / folded gastric retention system 540A is formed.

[0144] FIG. 5B shows a sheathed compressed / folded gastroretention system 540B that is encapsulated with a two-piece capsule. In this figure, the sheathed compressed / folded gastroretention system 540B is sheathed on the core side of the gastroretention system, similar to that of the sheathed compressed / folded gastroretention system 540A of FIG. 5A. The cap 516B of the two-piece capsule is placed on the sheath (i.e., on the core side of the gastroretention system) of the sheathed compressed / folded gastroretention system 540B. The body 514B of the two-piece capsule is placed on the arm side of the compressed / folded gastroretention system. When both the cap 516B and the body 514B (i.e., both pieces of the two-piece capsule) are placed on the sheathed compressed / folded gastroretention system 540B, an encapsulated gastroretention dosage form 542 is formed. Moreover, the cap 516B and the body 514B may overlap to some extent to form a seal that protects the encapsulated gastroretentive dosage form 542B from the external environment.

[0145] Also shown in Figure 5C is a sheathed compressed / folded gastric retention system 540C encapsulated in a two-piece capsule. However, unlike the sheathed compressed / folded gastric retention system 540B of Figure 5B, the sheathed compressed / folded gastric retention system 540C is encapsulated in a two-piece capsule such that the body of the two-piece capsule, body 514C, encases the sheath of the sheathed compressed / folded gastric retention system 540C. The cap of the two-piece capsule, cap 516C, is disposed on the arm side of the compressed / folded gastric retention system. The cap 516C and body 514C may overlap to some extent to form a seal that protects the encapsulated gastric retention dosage form 542B from the external environment.

[0146] Capsule Coatings for Gastric Retentive Dosage Forms Capsule coatings for gastroretentive systems are described below. The capsule coatings described below may be used to delay dissolution / opening of the capsule, particularly when the gastroretentive dosage form is in the esophagus. In some embodiments, the capsule coatings described below may accelerate capsule opening when the gastroretentive dosage form is in the stomach. The capsule coatings, as described below, may provide a protective moisture barrier, aid dissolution in the stomach, aid transit through the esophagus, and may provide a more comfortable administration experience for the patient.

[0147] The capsules described herein may be coated with a reverse enteric polymer with a low coefficient of static friction in some embodiments. Coating with a reverse enteric polymer with a low coefficient of static friction can help facilitate the passage of the coated capsule through the esophagus, minimizing the risk of pill-induced esophagitis. Specifically, the presence of a reverse enteric polymer and / or magnesium stearate in the coating can reduce the static friction coefficient of the dosage form. Certain drugs / APIs, such as doxycycline, tetracycline, clindamycin, other antibiotics, potassium chloride, bisphosphonates, and nonsteroidal anti-inflammatory drugs, are particularly prone to causing esophagitis. If some of these APIs cause esophagitis, it may pose a health risk. Therefore, ensuring that the capsule can easily pass through the esophagus can help prevent esophagitis.

[0148] In some embodiments, a reverse enteric polymer coating with a low coefficient of static friction may be applied to the outer surface of the dosage form. Suitable dosage forms may include, for example, tablets, capsules, or coated gastroretentive systems. In some embodiments, the coated dosage form may include a gastroretentive system with the API. In some embodiments, the coated dosage form may be an API without a gastroretentive system.

[0149] In some embodiments, the static friction coefficient of a dosage form coated with a low coefficient of static friction reverse enteric polymer coating may be less than the static friction coefficient of an uncoated dosage form. In some embodiments, the static friction coefficient of the coated dosage form may be 0.02 to 0.3 or 0.05 to 0.2. In some embodiments, the static friction coefficient of the coated dosage form may be less than 0.3, less than 0.25, less than 0.2, less than 0.15, less than 0.1, or less than 0.05. In some embodiments, the static friction coefficient of the coated dosage form may be greater than 0.02, greater than 0.05, greater than 0.1, greater than 0.15, greater than 0.2, or greater than 0.25.

[0150] In some embodiments

[0151]

number

[0152] may be 0.2 to 0.8.

[0153]

number

[0154] may be less than 0.8, less than 0.7, less than 0.6, less than 0.5, less than 0.4, or less than 0.3.

[0155]

number

[0156] may be greater than 0.2, greater than 0.3, greater than 0.4, greater than 0.5, greater than 0.6, or greater than 0.7.

[0157] In some embodiments, the static friction coefficient of the coated dosage form may be 5-80%, 20-80%, or 50-80% of the static friction coefficient of the uncoated dosage form. In some embodiments, the static friction coefficient of the coated dosage form may be less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the static friction coefficient of the uncoated dosage form. In some embodiments, the static friction coefficient of the coated dosage form may be greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, or greater than 70% of the static friction coefficient of the uncoated dosage form. In some embodiments, the static friction coefficient of the coated dosage form may be 0.05-0.35, or 0.1-0.2 less than the static friction coefficient of the uncoated dosage form. In some embodiments, the static coefficient of friction of the coated dosage form may be less than 0.35, less than 0.3, less than 0.25, less than 0.2, less than 0.15, less than 0.1, or less than 0.08 less than the static coefficient of friction of the uncoated dosage form. In some embodiments, the static coefficient of friction of the coated dosage form may be more than 0.05, more than 0.08, more than 0.1, more than 0.15, more than 0.2, more than 0.25, or more than 0.3 less than the static coefficient of friction of the uncoated dosage form.

[0158] For example, a gastroretentive dosage form comprising a coated capsule may release a gastroretentive system upon exposure to an aqueous pH 7.0 environment (i.e., an esophageal environment) and cause the gastroretentive system to assume an open configuration within a first time period. In some embodiments, an uncoated gastroretentive dosage form comprising an uncoated capsule may release a gastroretentive system upon exposure to an aqueous pH 7.0 environment and cause the gastroretentive system to assume an open configuration within a second time period. The first time period may in some embodiments be 15 seconds to 20 minutes, 1 minute to 15 minutes, or 1 minute to 10 minutes longer than the second time period. The first time period may in some embodiments be more than 15 seconds, more than 30 seconds, more than 45 seconds, more than 1 minute, more than 3 minutes, more than 5 minutes, more than 8 minutes, more than 10 minutes, more than 12 minutes, or more than 15 minutes longer than the second time period. The first time period may be less than 20 minutes, less than 18 minutes, less than 15 minutes, less than 12 minutes, less than 10 minutes, less than 8 minutes, less than 5 minutes, less than 3 minutes, less than 1 minute, less than 45 seconds, or less than 30 seconds longer than the second time period in some embodiments. The compositional characteristics of the gastric retention dosage form comprising a coated capsule and the uncoated gastric retention dosage form comprising an uncoated capsule may be identical except for the coating (e.g., the compositional characteristics of the capsule, the compositional characteristics of the gastric retention system, and the compositional characteristics of the sheath, if present). As described above, the gastric retention dosage form comprising a coated capsule has a capsule coating according to the embodiments provided herein. The uncoated gastric retention dosage form comprising an uncoated capsule does not have a capsule coating.

[0159] In some embodiments, a gastroretentive dosage form comprising a coated capsule may release the gastroretentive system upon exposure to an aqueous pH 3.0 environment (i.e., the stomach environment) and cause the gastroretentive system to assume an open configuration within a third time. In some embodiments, an uncoated gastroretentive dosage form comprising an uncoated capsule may release the gastroretentive system upon exposure to an aqueous pH 3.0 environment and cause the gastroretentive system to assume an open configuration within a fourth time. The third time may in some embodiments be 15 seconds to 20 minutes, 1 minute to 15 minutes, or 1 minute to 10 minutes longer than the fourth time. The third time may in some embodiments be more than 15 seconds, more than 30 seconds, more than 45 seconds, more than 1 minute, more than 3 minutes, more than 5 minutes, more than 8 minutes, more than 10 minutes, more than 12 minutes, or more than 15 minutes longer than the fourth time. The third time period may in some embodiments be less than 20 minutes, less than 18 minutes, less than 15 minutes, less than 12 minutes, less than 10 minutes, less than 8 minutes, less than 5 minutes, less than 3 minutes, less than 1 minute, less than 45 seconds, or less than 30 seconds longer than the fourth time period. The compositional characteristics of a gastric retention dosage form comprising a coated capsule and an uncoated gastric retention dosage form comprising an uncoated capsule may be identical except for the coating (e.g., compositional characteristics of the capsule, compositional characteristics of the gastric retention system, compositional characteristics of the sheath, if present). As described above, a gastric retention dosage form comprising a coated capsule has a capsule coating according to the embodiments provided herein. An uncoated gastric retention dosage form comprising an uncoated capsule does not have a capsule coating.

[0160] The capsule coating compositions provided herein can delay the time at which the gastroretentive dosage form releases the gastroretentive system and causes the gastroretentive system to assume an open configuration to help prevent rapid development in the patient's esophagus (i.e., pH 7.0). The coated gastroretentive dosage form can, for example, release the gastroretentive system and cause the gastroretentive system to assume an open configuration after 20-120 minutes, 30-90 minutes, or 40-60 minutes of residence in the aqueous pH 7.0 environment. The coated gastroretentive dosage form can, for example, release the gastroretentive system and cause the gastroretentive system to assume an open configuration after less than 120 minutes, less than 100 minutes, less than 80 minutes, less than 60 minutes, less than 50 minutes, less than 40 minutes, or less than 30 minutes of residence in the aqueous pH 7.0 environment. The coated gastroretentive dosage form may, for example, reside in the aqueous pH 7.0 environment for more than 20 minutes, more than 30 minutes, more than 40 minutes, more than 50 minutes, more than 60 minutes, more than 80 minutes, or more than 100 minutes before releasing the gastroretentive system and causing the gastroretentive system to assume an open configuration. The time it takes for the coated gastroretentive dosage form to open in the esophagus may be longer than the time it takes for the coated gastroretentive dosage form to travel from the patient's mouth, through the patient's esophagus, and into the patient's stomach.

[0161] The capsule coatings provided herein have also been developed to facilitate rapid dissolution / opening of the capsule and thus rapid release of the gastroretentive system encapsulated within the capsule. As discussed above, rapid opening of the capsule and rapid release of the gastroretentive system in the stomach (e.g., pH 1.5-3.0) can help prevent the gastroretentive dosage form from passing through the pyloric valve without opening. However, in some embodiments, the coated gastroretentive dosage form may release the gastroretentive system after 10 seconds to 30 minutes, 30 seconds to 20 minutes, 1 minute to 10 minutes residence in an aqueous pH 3.0 environment, allowing the gastroretentive system to assume an open configuration. In some embodiments, the coated gastroretentive dosage form may release the gastroretentive system and allow the gastroretentive system to assume an open configuration after residence in the aqueous pH 3.0 environment for more than 10 seconds, more than 20 seconds, more than 30 seconds, more than 40 seconds, more than 50 seconds, more than 1 minute, more than 2 minutes, more than 3 minutes, more than 4 minutes, more than 5 minutes, more than 10 minutes, more than 15 minutes, more than 20 minutes, or more than 25 minutes. In some embodiments, the coated gastroretentive dosage form may release the gastroretentive system and allow the gastroretentive system to assume an open configuration after residence in the aqueous pH 3.0 environment for less than 30 minutes, less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, less than 5 minutes, less than 4 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, less than 50 seconds, less than 40 seconds, less than 30 seconds, or less than 20 seconds.

[0162] Capsule coatings according to embodiments provided herein may include polymers, plasticizers, anti-adherents, and / or hydration aids.

[0163] In some embodiments, the polymer may be a reverse enteric polymer. The reverse enteric polymer may facilitate dissolution of the capsule in the gastric environment (e.g., pH 1.5-3.0). The reverse enteric polymer may also provide a moisture barrier to the capsule. A suitable reverse enteric polymer may have desirable physiochemical solubility properties, good film forming ability, and may be suitable for drug coating methods (e.g., pan-coating). In some embodiments, polymethacrylates are suitable reverse enteric polymers. For example, Eudragit® polymers may be suitable in some embodiments. Eudragit® polymers include a wide variety of polymethacrylate-based copolymers that are specifically formulated to facilitate targeted drug release. In some embodiments, Eudragit® E may be a suitable reverse enteric polymer. Eudragit® E dissolves in gastric fluids, particularly at pH 5.0 or below, due to the formation of salts at the tertiary amine groups. Thus, Eudragit® E can provide a suitable moisture barrier in neutral pH environments (i.e., in the mouth and esophagus), but dissolves easily in acidic pH environments (i.e., in the stomach). However, other materials may also be suitable as reverse enteric polymers, such as those that ionize and / or solubilize in acidic environments to increase the rate of moisture penetration (access to the underlying capsule or coating layer). However, pH dependence is not required of the polymer itself, but may be achieved by adding other excipients to the coating formulation. The coating formulation may, for example, include small molecule additives that have enhanced solubility at low pH (e.g., tertiary amines, imidazole-containing chemical entities, etc.). In some embodiments, the dry capsule coating composition on the capsule may include 40-95%, 50-80%, 60-70% by weight of polymer based on total solids. In some embodiments, the dry capsule coating composition on the capsule may comprise less than 95% by weight, less than 90% by weight, less than 85% by weight, less than 80% by weight, less than 75% by weight, less than 70% by weight, less than 65% by weight, less than 60% by weight, less than 55% by weight, less than 50% by weight, or less than 45% by weight of polymer based on total solids.In some embodiments, the dry capsule coating composition on the capsule may comprise greater than 40% by weight, greater than 45% by weight, greater than 50% by weight, greater than 55% by weight, greater than 60% by weight, greater than 65% by weight, greater than 70% by weight, greater than 75% by weight, greater than 80% by weight, greater than 85% by weight, or greater than 90% by weight of polymer based on total solids.

[0164] In some embodiments, the liquid capsule coating composition (i.e., before drying on the surface of the capsule, it is liquid) may comprise 3-30% polymer, 5-25% polymer, 5-20% polymer by weight. In some embodiments, the liquid capsule coating composition may comprise more than 3%, more than 5%, more than 8%, more than 10%, more than 12%, more than 15%, more than 18%, more than 20%, or more than 25% polymer by weight. In some embodiments, the liquid capsule coating composition may comprise less than 30%, less than 28%, less than 25%, less than 23%, less than 20%, less than 18%, less than 15%, less than 12%, less than 10%, less than 8%, or less than 5% polymer by weight.

[0165] Plasticizers in coating formulations can reduce brittleness by enhancing flexibility, elasticity, and adhesion of the coating to the underlying capsule surface. Suitable plasticizers can include phthalates, phosphates, citrates, tartrates, adipates, sebacates, sulfonamides, succinates, glycolates, glycerolates, benzoates, myristates, phenyl halides, and poloxamers. Specific compounds that can be used as plasticizers in coating formulations can include triacetin, triethyl citrate, polyethylene glycol, and dibutyl sebacate. In some embodiments, the dry capsule coating composition on the capsule can include 1-30%, 1-20%, or 1-10% by weight of plasticizer based on total solids. In some embodiments, the dry capsule coating composition on the capsule may comprise less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, or less than 2% by weight of plasticizer based on total solids. In some embodiments, the dry capsule coating composition on the capsule may comprise more than 1%, more than 2%, more than 3%, more than 4%, more than 5%, more than 6%, more than 7%, more than 8%, more than 9%, more than 10%, more than 15%, more than 20%, or more than 25% by weight of plasticizer based on total solids.

[0166] In some embodiments, the liquid capsule coating composition (i.e., before drying on the surface of the capsule, it is liquid) may comprise 0.1-5.0%, 0.2-3.0%, 0.3-1.0% by weight of plasticizer. In some embodiments, the liquid capsule coating composition may comprise more than 0.1%, more than 0.2%, more than 0.3%, more than 0.4%, more than 0.5%, more than 0.6%, more than 0.7%, more than 0.8%, more than 0.9%, more than 1.0%, more than 1.5%, more than 2.0%, more than 2.5%, more than 3.0%, or more than 4.0% by weight of plasticizer. In some embodiments, the liquid capsule coating composition may comprise less than 5.0 wt%, less than 4.0 wt%, less than 3.5 wt%, less than 3.0 wt%, less than 2.5 wt%, less than 2.0 wt%, less than 1.5 wt%, less than 1.0 wt%, less than 0.9 wt%, less than 0.8 wt%, less than 0.7 wt%, less than 0.6 wt%, less than 0.5 wt%, less than 0.4 wt%, less than 0.3 wt%, or less than 0.2 wt% plasticizer.

[0167] Anti-adherents in capsule coating formulations may help prevent the capsules from becoming sticky during processing and storage. Moreover, certain anti-adherents can improve the lubrication ability of the coated capsules and provide a glossy, smooth surface finish. Suitable anti-adherents may include bulk agents (such as talc) and surface agents (such as magnesium stearate). In some embodiments, magnesium stearate can be particularly useful in helping to reduce the static coefficient of friction of the coated, encapsulated gastroretentive system. In some embodiments, coatings including magnesium stearate can reduce the static coefficient of friction to as low as 0.1 or

[0168]

number

[0169] The coefficient of static friction may be reduced to 0.4 or less. A coated encapsulated gastroretentive system with a reduced coefficient of static friction may aid in the passage of the dosage form through the patient's esophagus and minimize the possibility of pill-induced esophagitis. In some embodiments, the dry capsule coating composition on the capsule may comprise 1-40%, 1-25%, or 1-10% by weight of anti-adherent agent based on total solids. In some embodiments, the dry capsule coating composition on the capsule may comprise less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, or less than 2% by weight of anti-adherent agent based on total solids. In some embodiments, the dry capsule coating composition on the capsule may comprise greater than 1%, greater than 2%, greater than 3%, greater than 4%, greater than 5%, greater than 6%, greater than 7%, greater than 8%, greater than 9%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, or greater than 35% by weight of anti-adherent agent based on total solids.

[0170] In some embodiments, the liquid capsule coating composition (i.e., before drying on the surface of the capsule, it is liquid) may comprise 0.1-5.0%, 0.2-3.0%, or 0.3-1.0% by weight of anti-blocking agent. In some embodiments, the liquid capsule coating composition may comprise more than 0.1%, more than 0.2%, more than 0.3%, more than 0.4%, more than 0.5%, more than 0.6%, more than 0.7%, more than 0.8%, more than 0.9%, more than 1.0%, more than 1.5%, more than 2.0%, more than 2.5%, more than 3.0%, or more than 4.0% by weight of anti-blocking agent. In some embodiments, the liquid capsule coating composition may comprise less than 5.0 wt%, less than 4.0 wt%, less than 3.5 wt%, less than 3.0 wt%, less than 2.5 wt%, less than 2.0 wt%, less than 1.5 wt%, less than 1.0 wt%, less than 0.9 wt%, less than 0.8 wt%, less than 0.7 wt%, less than 0.6 wt%, less than 0.5 wt%, less than 0.4 wt%, less than 0.3 wt%, or less than 0.2 wt% anti-blocking agent.

[0171] The capsule coating composition according to the embodiments provided herein may include a hydration aid. The hydration aid may help to speed up the dissolution of the capsule in the gastric environment by promoting hydration. Suitable hydration aids may include Kollidon PVP12, Kollidon VA64, PEG1000, low viscosity hydroxypropyl methylcellulose, and crystalline mannitol. In some embodiments, the dry capsule coating composition on the capsule may include 2-50%, 5-40%, or 10-30% by weight of the hydration aid based on the total solids. In some embodiments, the dry capsule coating composition on the capsule may include less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% by weight of the hydration aid based on the total solids. In some embodiments, the dry capsule coating composition on the capsule may comprise more than 2% by weight, more than 5% by weight, more than 10% by weight, more than 15% by weight, more than 20% by weight, more than 25% by weight, more than 30% by weight, more than 35% by weight, more than 40% by weight, or more than 45% by weight of hydration adjuvant based on total solids.

[0172] In some embodiments, the liquid capsule coating composition (i.e., prior to drying on the surface of the capsule, being liquid) may comprise 0.1-5.0%, 0.2-3.0%, or 0.3-1.0% by weight of a hydration aid. In some embodiments, the liquid capsule coating composition may comprise greater than 0.1%, greater than 0.2%, greater than 0.3%, greater than 0.4%, greater than 0.5%, greater than 0.6%, greater than 0.7%, greater than 0.8%, greater than 0.9%, greater than 1.0%, greater than 1.5%, greater than 2.0%, greater than 2.5%, greater than 3.0%, or greater than 4.0% by weight of a hydration aid. In some embodiments, the liquid capsule coating composition may comprise less than 5.0 wt%, less than 4.0 wt%, less than 3.5 wt%, less than 3.0 wt%, less than 2.5 wt%, less than 2.0 wt%, less than 1.5 wt%, less than 1.0 wt%, less than 0.9 wt%, less than 0.8 wt%, less than 0.7 wt%, less than 0.6 wt%, less than 0.5 wt%, less than 0.4 wt%, less than 0.3 wt%, or less than 0.2 wt% of a hydration adjuvant.

[0173] The capsule coating composition according to embodiments provided herein may be soluble in a variety of solvents. The capsule coating composition may be soluble in, for example, aqueous and / or organic solvents. Examples of suitable solvents include isopropyl alcohol, acetone, and ethyl acetate. In some embodiments, the liquid coating composition in the solvent may comprise 55-97% by weight of the solvent. In some embodiments, the liquid coating composition in the solvent may comprise more than 55% by weight, more than 60% by weight, more than 65% by weight, more than 70% by weight, more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, or more than 95% by weight of the solvent. In some embodiments, the liquid coating composition in the solvent may comprise less than 97% by weight, less than 95% by weight, less than 90% by weight, less than 85% by weight, less than 80% by weight, less than 75% by weight, less than 70% by weight, less than 65% by weight, or less than 60% by weight of the solution.

[0174] The capsule coating composition according to the embodiments provided herein may include additional ingredients other than those already mentioned above. For example, a pH-modifying buffer may be used to help promote dissolution of the coating in weak acid (i.e., in the gastric environment). Examples of pH-modifying buffers may include imidazole-based buffers or imidazole titrated with carboxylic acid or histide buffer systems. Other ingredients that may be included in the coating composition may include, but are not limited to, colorants, flavors, opacifiers, and preservatives.

[0175] In addition to the capsule coating, the gastroretentive dosage form comprising the sheath may also include a sheath coating. Much like the capsule coating composition described above, the sheath coating composition may promote dissolution in the gastric environment. In some embodiments, the sheath coating composition and the capsule coating composition may be the same. In some embodiments, the sheath coating composition may include a hydration aid to shorten the sleeve dissolution time in the gastric environment and release the gastroretentive system quickly in the patient's stomach. In some embodiments, the sheath coating composition may include a hydrophilic polymer and / or a hygroscopic polymer or alternatively a hygroscopic wetting agent or water retaining agent. Examples of polymers may include polysaccharide-based polymers such as hydroxypropylmethylcellulose, carboxymethylcellulose, starch, pectin, chitosan, alginates, other natural or semi-synthetic polymers such as gelatin, collagen, silk fibroin, and / or non-cellulosic synthetic polymers such as polyethylene glycol, polyethyl glycol-polypropylene glycol di- and triblock copolymers, polyvinylpyrrolidone and derivatives thereof. Non-polymeric materials may include sugars such as polysorbates, glycerol, propanediol, sucrose, glucose, dextrose, mannitol, maltitol, mannose and various salts.

[0176] Figures 6A-6D show steps of the encapsulation and coating process according to some embodiments. In Figure 6A, gastro-retention system 610 is shown in a folded configuration. In Figure 6B, gastro-retention system 610 is shown restrained in a folded configuration by a sheath 612. In Figure 6C, the sheathed gastro-retention system is fully encapsulated in a capsule (including body 614 and cap 616). In Figure 6D, a two-piece capsule (including body 614 and cap 616) is shown coated with capsule coating 620.

[0177] Coated and Encapsulated Gastroretentive Systems The following describes a coating composition for coating the folded gastroretentive system: In some embodiments, the coating composition may include a polymer, a plasticizer, a gelling agent, and / or a solvent.

[0178] As used herein, the term "coating" may also refer to "enrobing." "Coating" includes surrounding the folded gastroretentive system with a softgel-type shell material to form a "coated gastroretentive system." "Coating" may also refer to a coating applied to the outside of a coated gastroretentive device.

[0179] A coating composition for coating a gastric retention system has been developed according to the embodiments provided herein to enhance the deployment performance of the gastric retention system. Specifically, a coating composition for coating a gastric retention system has been developed to maintain the gastric retention system in a compressed form between the time of administration and the time of reaching the stomach. The coating is designed to dissolve rapidly once the gastric retention dosage form reaches the stomach. The use of a rapidly dissolving coating can ensure the release of the gastric retention system inside the stomach before passing through the pyloric valve.

[0180] Coated gastroretentive dosage forms may offer various advantages over conventional capsule-encapsulated gastroretentive systems. As mentioned above, the use of a coating to coat the folded gastroretentive system according to the embodiments provided herein may protect the therapeutic agent (and in this case, the gastroretentive system) from adverse changes. Moreover, coated gastroretentive dosage forms may be easier to swallow than gastroretentive systems that are simply encapsulated in a conventional capsule, and may reduce transit time in the esophagus, helping to minimize any chance of the gastroretentive system being released and unfolding in the esophagus.

[0181] Moreover, coating the gastroretentive system with a coating composition according to the embodiments provided herein allows for a smooth, non-sticky surface for ease of swallowing (prevents esophageal retention), and allows for non-greasy, flawless processing, storage and transportation steps.

[0182] As mentioned above, the coating composition according to the embodiments provided herein is designed to protect the patient from development in the esophagus. The development time of the coated gastric retention dosage form in an aqueous pH 7.0 environment (i.e., about the pH of the esophagus) may be, for example, 15 to 120 minutes, 20 to 60 minutes, or 20 to 30 minutes. In some embodiments, the development time of the coated gastric retention dosage form in an aqueous pH 7.0 environment may be less than 120 minutes, less than 100 minutes, less than 80 minutes, less than 60 minutes, less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 25 minutes, or less than 20 minutes. In some embodiments, the development time of the coated gastric retention dosage form in an aqueous pH 7.0 environment may be more than 15 minutes, more than 20 minutes, more than 25 minutes, more than 30 minutes, more than 40 minutes, more than 50 minutes, more than 60 minutes, more than 80 minutes, or more than 100 minutes.

[0183] The coating composition according to the embodiments provided herein may also be designed to dissolve quickly in the stomach environment. As mentioned above, once the gastric retention dosage form reaches the stomach, it should dissolve quickly to develop the gastric retention system in the stomach. If the coating material fails to dissolve quickly, there is a risk that the gastric retention dosage form will pass through the pyloric valve before releasing the gastric retention system. Therefore, the coating composition according to the embodiments provided herein is designed to dissolve quickly and consistently. In some embodiments, the dissolution of the coating material is less or not reliable at low pH.

[0184] For example, the coated gastroretentive dosage form may unfold after 1-60 minutes, 5-45 minutes, or 10-30 minutes residence in the aqueous pH 3.0 environment. In some embodiments, the coated gastroretentive dosage form may unfold after more than 1 minute, more than 2 minutes, more than 3 minutes, more than 4 minutes, more than 5 minutes, more than 10 minutes, more than 15 minutes, more than 20 minutes, more than 25 minutes, more than 30 minutes, more than 35 minutes, more than 40 minutes, more than 45 minutes, more than 50 minutes, or more than 55 minutes residence in the aqueous pH 3.0 environment. In some embodiments, the coated gastroretentive dosage form may unfold after less than 60 minutes, less than 55 minutes, less than 50 minutes, less than 45 minutes, less than 40 minutes, less than 35 minutes, less than 30 minutes, less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, less than 5 minutes, less than 4 minutes, less than 3 minutes, or less than 2 minutes residence in the aqueous pH 3.0 environment.

[0185] The thickness of the coating covering the gastric retention device in its folded configuration may vary depending on the desired properties of the coated gastric retention dosage form (e.g., deployment time). In some embodiments, the thickness of the coating covering the folded gastric retention system may be 50-700 μm or 150-350 μm thick. In some embodiments, the thickness of the coating covering the folded gastric retention system may be greater than 50 μm, greater than 100 μm, greater than 150 μm, greater than 200 μm, greater than 250 μm, greater than 300 μm, greater than 350 μm, greater than 400 μm, greater than 450 μm, greater than 500 μm, greater than 550 μm, greater than 600 μm, or greater than 650 μm thick. In some embodiments, the coating covering the folded gastroretention system may be less than 700 μm, less than 650 μm, less than 600 μm, less than 550 μm, less than 500 μm, less than 450 μm, less than 400 μm, less than 350 μm, less than 300 μm, less than 250 μm, less than 200 μm, less than 150 μm, or less than 100 μm thick. In some embodiments, the coating covering the folded gastroretention system may provide an airtight seal. The coating may, for example, hermetically seal the folded gastroretention system to form a coated gastroretention dosage form. In some embodiments, the coating for covering the folded gastroretention system may comprise a softgel-type shell material.

[0186] Coating compositions according to embodiments provided herein may include a polymer, a plasticizer, a gelling agent, and / or water.

[0187] In some embodiments, the polymer may be an aqueous polymer dispersion or a pH-responsive polymer, such as a reverse-enteric polymer. Suitable aqueous polymer dispersions include Kollicoat® Smartseal. Reverse-enteric polymers may aid in dissolution of the coating in the gastric environment and may provide a moisture barrier for gastroretentive systems. Reverse-enteric polymers may also have desirable physiochemical solubility properties, good film-forming ability, and may be suitable for drug coating methods (e.g., pan-coating). In some embodiments, polymethacrylates are suitable reverse-enteric polymers. For example, Eudragit® polymers may be suitable for some embodiments. Eudragit® polymers include a wide variety of polymethacrylate-based copolymers that are specifically formulated to promote targeted drug release. Eudragit® E, a specific type of polymethacrylate, may be a suitable reverse-enteric polymer. Eudragit® E is particularly soluble in gastric juices due to the formation of salts at tertiary amine groups at pH 5.0 or below. Thus, Eudragit® E can provide a suitable moisture barrier in neutral pH environments (i.e., in the mouth and esophagus). Other materials may also be suitable as reverse enteric polymers, such as those that ionize and / or solubilize in acidic environments to increase the rate of moisture penetration (access to the underlying capsule or coating layer). However, pH dependence is not required of the polymer itself, but may be achieved by adding other excipients to the coating formulation. The coating formulation may, for example, include small molecule additives that have enhanced solubility at low pH (e.g., tertiary amines, imidazole-containing chemical entities, etc.). In some embodiments, the coating composition may include 10-70% by weight, 20-60% by weight, or 30-50% by weight of the polymer. In some embodiments, the coating composition may comprise less than 70% by weight, less than 65% by weight, less than 60% by weight, less than 55% by weight, less than 50% by weight, less than 45% by weight, less than 40% by weight, less than 35% by weight, less than 30% by weight, less than 25% by weight, less than 20% by weight, or less than 15% by weight of polymer.In some embodiments, the coating composition may comprise greater than 10% by weight, greater than 15% by weight, greater than 20% by weight, greater than 25% by weight, greater than 30% by weight, greater than 35% by weight, greater than 40% by weight, greater than 45% by weight, greater than 50% by weight, greater than 55% by weight, greater than 60% by weight, greater than 65% by weight, greater than 70% by weight, greater than 75% by weight, greater than 80% by weight, or greater than 85% by weight of polymer.

[0188] The plasticizer in the coating composition can enhance the flexibility and elasticity of the coated gastroretentive dosage form, thereby reducing brittleness. Suitable plasticizers can include phthalates, phosphates, citrates, tartrates, adipates, sebacates, sulfonamides, succinates, glycolates, glycerolates, benzoates, myristates, polyols, phenyl halides, and poloxamers. Specific compounds that can be used as plasticizers in the coating formulation can include triacetin, triethyl citrate, polyethylene glycol, and dibutyl sebacate, glycerin, or sorbitol. In some embodiments, the coating composition can include 10-70% by weight, 20-60% by weight, or 30-50% by weight of plasticizer. In some embodiments, the coating composition may comprise less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, or less than 15% by weight of plasticizer. In some embodiments, the coating composition may comprise more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, or more than 85% by weight of plasticizer.

[0189] The coating composition according to the embodiments provided herein includes a gelling agent. Suitable gelling agents can include, for example, gelatin, pullulan, hydroxypropyl methylcellulose, and / or potato starch. If gelatin is used as the gelling agent, the bloom strength of the gelatin can be 100-300, or 150-250. In some embodiments, the bloom strength of the gelatin can be greater than 100, greater than 150, greater than 200, or greater than 250. In some embodiments, the bloom strength of the gelatin can be less than 300, less than 250, less than 200, or less than 150.

[0190] In some embodiments, the coating composition may comprise 30-80%, 40-70%, 50-60% by weight of gelling agent. In some embodiments, the coating composition may comprise less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, or less than 35% by weight of gelling agent. In some embodiments, the coating composition may comprise more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, or more than 75% by weight of gelling agent.

[0191] Coating compositions according to embodiments provided herein may additionally comprise water. The coating compositions may comprise 1-30 wt%, 5-25 wt%, or 10-20 wt% water. In some embodiments, the coating compositions may comprise less than 30 wt%, less than 25 wt%, less than 20 wt%, less than 15 wt%, less than 10 wt%, or less than 5 wt% water. In some embodiments, the coating compositions may comprise more than 1 wt%, more than 5 wt%, more than 10 wt%, more than 15 wt%, more than 20 wt%, or more than 25 wt% water.

[0192] Coating compositions according to embodiments provided herein may include additional ingredients other than those already mentioned above. For example, opacifiers, colorants, fragrances, and / or preservatives may also be used in the coating compositions described herein. Suitable opacifiers may include titanium dioxide. Suitable colorants may include FDA approved dyes and the like. Suitable fragrances include ethyl vanillin or sucrose. Suitable preservatives include parabens, such as methylparaben or propylparaben.

[0193] Encapsulation and Coating Process The gastroretentive system may be encapsulated and / or coated using any suitable encapsulation and / or coating technique. In Figure 7, a schematic diagram illustrating a method 600 for preparing a gastroretentive dosage form according to some embodiments is provided.

[0194] In step 702 of the method for preparing a gastroretentive dosage form, the folded gastroretentive system is encapsulated in a capsule. Step 702 of the method may specifically include folding the gastroretentive system and inserting the folded gastroretentive system into a container. Step 702 may be performed manually or mechanically. Folding the gastroretentive system may include compressing or pressing the gastroretentive system into the folded form. Inserting the gastroretentive system into a container may include inserting the compressed gastroretentive system into a capsule or other container of an appropriate size.

[0195] In some embodiments, the method of preparing a gastric retention dosage form may include receiving a foldable gastric retention system in an unfolded configuration. The foldable gastric retention system may be received, for example, by a vibratory bowl feeder or a pick-and-place conveyor. In some embodiments, the method of preparing a gastric retention dosage form may include orienting the gastric retention system to a folded position. The method may also include folding the gastric retention system into a folded configuration. Once the gastric retention dosage form is in the folded configuration, the folded gastric retention dosage form may be inserted into an opening of a container. The process of encapsulating a gastric retention system is provided in further detail in International Application PCT / US2018 / 051816, which is incorporated herein by reference in its entirety.

[0196] In step 704 of the method for preparing a gastroretentive dosage form, the encapsulated gastroretentive system may be coated with a reverse enteric coating.

[0197] For example, a pan coating process may be used to coat the encapsulated gastroretention system. In some embodiments, a LDCS 48098 / Freund-Vector pan coater with a 1.5 L pan size may be used in conjunction with a SCHLICK ABC LDCS-FP HCC-6869-3 spray gun and peroxide-cured silicone pump tubing to coat the encapsulated gastroretention system. In some embodiments, empty capsules may be coated prior to being used to encapsulate the gastroretention system.

[0198] During the pan coating process, several process conditions may be specified. The process conditions include inlet temperature, outlet temperature, coater air flow, pan speed, pump speed, atomizing pressure, pattern pressure, spray rate, drying pan speed, and drying time in the pan. The inlet temperature may be, for example, 30-70°C, 35-65°C, or 40-60°C. In some embodiments, the inlet temperature may be less than 70°C, less than 65°C, less than 60°C, less than 55°C, less than 50°C, or less than 45°C. In some embodiments, the inlet temperature may be greater than 30°C, greater than 35°C, greater than 40°C, greater than 45°C, or greater than 50°C.

[0199] The outlet temperature may be between 20° C. and 60° C., between 25° C. and 50° C., or between 30° C. and 40° C. In some embodiments, the outlet temperature may be less than 60° C., less than 50° C., less than 40° C., or less than 30° C. In some embodiments, the outlet temperature may be greater than 20° C., greater than 30° C., greater than 40° C., or greater than 50° C.

[0200] The coater air flow may be 20-80 cubic feet per minute (CFM) (×0.472 cubic meters per second m3 / s), 30-70 CFM, or 40-60 CFM. In some embodiments, the coater air flow may be less than 80 CFM, less than 70 CFM, less than 60 CFM, less than 50 CFM, or less than 40 CFM. In some embodiments, the coater air flow may be greater than 20 CFM, greater than 30 CFM, greater than 40 CFM, greater than 50 CFM, or greater than 60 CFM.

[0201] The pan speed may be 10-50 rpm, 15-40 rpm, or 20-30 rpm. In some embodiments, the pan speed may be greater than 10 rpm, greater than 15 rpm, greater than 20 rpm, greater than 30 rpm, or greater than 40 rpm. In some embodiments, the pan speed may be less than 50 rpm, less than 40 rpm, less than 30 rpm, less than 20 rpm, or less than 15 rpm.

[0202] The pump speed may be between 2 and 15 rpm, between 3 and 12 rpm, or between 5 and 10 rpm. In some embodiments, the pump speed may be greater than 2 rpm, greater than 3 rpm, greater than 5 rpm, or greater than 10 rpm. In some embodiments, the pump speed may be less than 15 rpm, less than 12 rpm, less than 10 rpm, or less than 5 rpm.

[0203] The spray pressure may be 10 to 40 pounds per square inch (psi) (kP), 15 to 35 psi, or 20 to 30 psi. In some embodiments, the spray pressure may be greater than 10 psi, greater than 15 psi, greater than 20 psi, or greater than 25 psi. In some embodiments, the spray pressure may be less than 40 psi, less than 35 psi, less than 30 psi, less than 25 psi, or less than 20 psi.

[0204] The pattern pressure may be between 10 and 40 psi (kP), between 15 and 35 psi, or between 20 and 30 psi. In some embodiments, the pattern pressure may be greater than 10 psi, greater than 15 psi, greater than 20 psi, or greater than 25 psi. In some embodiments, the pattern pressure may be less than 40 psi, less than 35 psi, less than 30 psi, less than 25 psi, or less than 20 psi.

[0205] The spray rate may be 1 to 10 grams per second (g / min), or 3 to 8 g / min. In some embodiments, the spray rate may be greater than 1 g / min, greater than 2 g / min, greater than 3 g / min, greater than 4 g / min, or greater than 5 g / min. In some embodiments, the spray rate may be less than 10 g / min, less than 8 g / min, less than 6 g / min, less than 5 g / min, or less than 4 g / min.

[0206] The drying pan speed may be 1-30 rpm, 3-20 rpm, or 5-10 rpm. In some embodiments, the drying pan speed may be greater than 1 rpm, greater than 2 rpm, greater than 3 rpm, greater than 4 rpm, greater than 5 rpm, greater than 8 rpm, greater than 10 rpm, or greater than 15 rpm. In some embodiments, the drying pan speed may be less than 30 rpm, less than 25 rpm, less than 20 rpm, less than 15 rpm, less than 10 rpm, less than 8 rpm, or less than 5 rpm.

[0207] The total drying time in the pan may be 15 to 120 minutes, 30 to 100 minutes, or 45 to 80 minutes. In some embodiments, the total drying time in the pan may be greater than 15 minutes, greater than 30 minutes, greater than 45 minutes, greater than 60 minutes, or greater than 80 minutes. In some embodiments, the total drying time in the pan may be less than 120 minutes, less than 100 minutes, less than 80 minutes, less than 60 minutes, or less than 45 minutes. In some embodiments, the drying time may be continuous. In some embodiments, the drying time may be intermittent.

[0208] The capsule coating may comprise 0.2-15%, 0.5-10%, or 1-5% by weight of the total gastric retention dosage form. In some embodiments, the capsule coating may comprise more than 0.2%, more than 0.5%, more than 0.8%, more than 1.0%, more than 1.5%, more than 2.0%, more than 2.5%, more than 3.0%, more than 3.5%, more than 4.0%, or more than 4.5% by weight of the total gastric retention dosage form. In some embodiments, the capsule coating may comprise less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1.0%, less than 0.8%, or less than 0.5% by weight of the total gastric retention dosage form. EXAMPLES

[0209] Provided below are various examples of capsules and capsule coatings according to embodiments provided herein.

[0210] Example 1: The following provides test data for various capsule coating compositions. Specifically, the data shows the effect that different types and amounts of hydration aids can have on capsule dissolution in both neutral (i.e., esophagus) and acidic (i.e., stomach) pH environments. The data also shows capsule stickiness upon storage, pan-coating processability observations, and static friction coefficient (i.e., effect on swallowing). The polymer used is Eudragit® E, the anti-tack agent is magnesium stearate, the plasticizer is triacetin, and the solvent used is isopropyl alcohol. The testing was performed according to the techniques discussed in more detail below.

[0211] [Table 1]

[0212] Example 2: Different types of capsules were tested for unfolding time. Both unsheathed and sheathed gastroretention systems were tested. In the sheathed gastroretention system, the sheath was attached to the arm side of the compressed / folded gastroretention system. As shown in Figure 2 below, gelatin capsules (Coni-Snap®), HPMC capsules (VCaps® Plus), and pullulan capsules (Plantcaps®) were tested. In addition to unfolding time, dissolution observations were also made. The sheath used is VCaps® Plus HPMC of size 0EL. The test was performed according to the technique discussed in more detail below.

[0213] [Table 2]

[0214] Example 3: The deployment time of a gastric retention system with filaments and sheathed on the arm side and a gastric retention system with filaments and sheathed on the core side were tested. Some gastric retention systems, particularly star-shaped gastric retention systems, are configured to be compressed / folded on the core. Thus, when compressed / folded, the gastric retention system has an arm side and a core side (e.g., as shown in Figures 2, 5A-5C, and 6A). In the examples described herein, the deployment time of a gastric retention system compressed and sheathed on the arm side and a gastric retention system compressed and sheathed on the core side were tested.

[0215] In Figures 8A-8G, different sheathed and encapsulated forms of gastric retention systems including filaments are shown. Specifically, in Figure 8A, a compressed / folded gastric retention system 810A is shown sheathed on the arm side with a sheath 812A. The compressed / folded gastric retention system 810A includes a filament between each arm of the gastric retention system. Thus, the filament of the gastric retention system is covered by the sheath 812A. In Figure 8B, gastric retention system 810A is shown sheathed on the arm side of the gastric retention system with a sheath 812A to form a sheathed compressed / folded gastric retention system 840B. In Figure 8C, a compressed / folded gastric retention system 810C is shown. However, the compressed / folded gastric retention system 810C is shown sheathed on the core side of the gastric retention system with a sheath 812C. In Figure 8D, a compressed / folded gastric retention system 810D is shown sheathed with a sheath 812C on the core side of the gastric retention system. Thus, unlike the sheathed compressed / folded gastric retention system 840B of Figure 8B, the webbing of the compressed / folded gastric retention system 810C is not covered by the sheath 812C in the sheathed compressed / folded gastric retention system 840D.

[0216] In Figures 8E and 8F, different encapsulation configurations of sheathed compressed / folded gastric retention systems are shown. Both sheathed compressed / folded gastric retention systems 840E in Figure 8E and sheathed compressed / folded gastric retention systems 840F in Figure 8F are sheathed on the arm side of the gastric retention system. Figure 8E also shows sheathed gastric retention system 840E encapsulated with a two-piece capsule. A two-piece capsule cap, cap 816E, is shown encapsulating the sheathed gastric retention system on the core side, and a two-piece capsule body, body 814E, is shown encapsulating the sheathed gastric retention system on the sheathed arm side. In Figure 8F, sheathed gastric retention system 840F encapsulated with a two-piece capsule is shown. However, unlike that of FIG. 8E, the sheathed compressed / folded gastric retention system 840F of FIG. 8F is encapsulated with a two-piece capsule body, body 814F, encapsulating the core side, and a two-piece capsule cap, cap 816F, encapsulating the sheathed arm side of the gastric retention system.

[0217] In FIG. 8G, a compressed / folded gastroretentive system 842G with an encapsulated sheath is shown.

[0218] The sheath used in these trials was VCaps® Plus HPMC size 0. The sheathed gastroretention systems were then encapsulated with a VCaps® Plus 00EL HPMC 2 piece capsule. Table 3 shows the deployment time data for the gastroretention systems with the sheath on the arm side, and Table 4 shows the deployment time data for the gastroretention systems with the sheath on the core side. The data in both Tables 3 and 4 were obtained using a deployment (rocker) test at pH 7, which is described in further detail below.

[0219] [Table 3]

[0220] [Table 4]

[0221] As shown in Tables 3 and 4, the deployment times of the core-side sheathed gastric retention systems and the arm-side sheathed gastric retention systems are similar. Although the average deployment time of the core-side sheathed gastric retention systems was slightly longer than the average deployment time of the arm-side sheathed gastric retention systems, this difference was not sufficient to be statistically significant. Thus, based on the data in Tables 3 and 4, the deployment times of the arm-side gastric retention systems and the core-side gastric retention systems may each be suitable and may provide similar results in some embodiments.

[0222] Example 4: The deployment time of a gastroretention system containing a coated capsule was tested using both sheathed and unsheathed gastroretention systems to evaluate the effect of sheath on deployment time. Based on the data reproduced in Table 5 below, the sheathed gastroretention system took approximately 6-7 additional minutes to deploy in both a pH 7.0 environment (i.e., esophagus) and a pH 3.0 environment (i.e., stomach). The sheath used in the sheathed gastroretention system was Size 0V Caps® Plus HPMC. This test was performed according to the techniques further detailed below.

[0223] [Table 5]

[0224] Example 5: Two different anti-adhesive agents, talc and magnesium stearate, were tested for static friction coefficient and spreading time. 22% talc by weight based on total solids was used, and 4.6% magnesium stearate by weight based on total solids was used. The polymer coating tested, which is inverse enteric and has a low static friction coefficient, can help increase the slipperiness of the dosage form when used to coat a capsule. Anti-adhesive agents, especially magnesium stearate, can also help increase the slipperiness of the dosage form by lowering its static coefficient. A slippery dosage form (i.e., a low static friction coefficient) can help minimize the risk of pill-induced esophagitis. This test was performed according to the technique described in more detail below.

[0225] Additionally, the static friction coefficient at 2 minutes for uncoated VCaps Plus HPMC capsules was 0.35±0.04. However, the static friction coefficient for VCaps® Plus HPMC capsules coated with a formulation containing Eudragit E, dibutyl sebacate, and magnesium stearate was 0.06±0.01. This data indicates that a reverse enteric coating of Eudragit E in the presence of magnesium stearate and dibutyl sebacate is effective in reducing friction during swallowing of HPMC capsules.

[0226] As shown in FIG. 9, both the talc-coated dosage form and the magnesium stearate-coated dosage form had a lower static friction coefficient when wet than the uncoated dosage form, indicating that the talc and magnesium stearate help make the dosage forms easier to swallow.

[0227] The results, in Table 6 below, show that both the talc-containing coating and the magnesium stearate-containing coating provide acceptable development times in both the mildly acidic gastric (i.e., pH 3.0) and esophageal (i.e., pH 7.0) environments.

[0228] [Table 6]

[0229] Example 6: Figures 10A and 10B show the relationship between the expansion time of a gastric retention dosage form and the total weight of the dosage form's coating. As shown in both figures, as the weight of the individual coatings of the gastric retention dosage form increases, the expansion time of the dosage form also increases. The data in both Figures 10A and 10B were obtained by conducting the expansion test at pH 3.0 (i.e., the mildly acidic stomach environment). The details of the expansion test are discussed in more detail below.

[0230] Example 7: Gastric retention dosage forms were dropped to determine how physical impact (e.g., from processing, shipping, etc.) affects unfolding time. Two groups of gastric retention dosage forms were tested; one group was dropped and one group was not. As shown in Figure 7, dropping the gastric retention dosage forms did not significantly affect the unfolding time of the gastric retention dosage forms in an aqueous pH 7.0 environment. This indicates that the coating is robust enough to maintain protection against unfolding in the esophagus even after being subjected to physical impact. Details of the drop and unfolding tests are discussed in more detail below.

[0231] [Table 7]

[0232] Example 8: A coated gastroretentive dosage form according to the embodiments provided herein was compared to an uncoated gastroretentive dosage form. In particular, the coated and uncoated gastroretentive dosage forms were tested in an aqueous pH 3.0 environment and an aqueous pH 7.0 environment. The results of this test are shown in FIG. 10. An uncoated gastroretentive dosage form was prepared using VCaps® Plus sheaths and VCaps® Plus capsules and coated with a reverse enteric coating according to the embodiments provided herein. The reverse enteric coating specifically included magnesium stearate as an anti-tack agent, Eudragit® EPO as a reverse enteric polymer, and dibutyl sebacate as a plasticizer. The reverse enteric coating did not include a hydration aid. The spreading test was performed in lactate buffer, and further details of the spreading test are provided below.

[0233] As shown in Figure 11, the expansion times of the coated gastric retention dosage form in both aqueous pH 3.0 and aqueous pH 7.0 environments were longer than the expansion time of the uncoated gastric retention dosage form in aqueous pH 3.0 environment. The expansion times of the uncoated gastric retention dosage form in aqueous pH 3.0 and aqueous 7.0 environments may be considered to be approximately the same.

[0234] Example 9: Two gelatin shell formulations were evaluated for coating of gastroretentive systems. The ingredients of the two formulations are provided in Table 8 below. The key difference between these two formulations was the bloom strength and the presence of low molecular weight (3-6 kD) gelatin hydrolysates. The presence of low molecular weight gelatin hydrolysates can speed up hydration. Prior to coating, the gastroretentive systems were folded / encapsulated into four different capsule and sheath configurations as shown in Figure 9 below. The coating process was performed on each of the folded configurations for both gelatin formulations.

[0235] [Table 8]

[0236] [Table 9]

[0237] The coated gastroretentive systems were evaluated for appearance, size, and timing of development at pH 3 (to simulate development at slightly acidic stomach pH conditions). Figure 12 shows the uncoated development times for both coated formulations. No significant differences were observed between the two formulations in terms of appearance and size. There was no significant difference in development time at pH 3 for sublots A and B. However, the development time at pH 3 for sublots C and D is more variable for formulation 1 with hydrolysate compared to formulation 2. Sublot C coated gastroretentive system shows the fastest development time for both formulations. All uncoated coated gastroretentive systems developed in less than 60 minutes at pH 3, except for formulation 1 - sublot D. Sublot D took 85 minutes to develop at pH 3.

[0238] The development time of the coated gastroretentive system of Sublot C was also evaluated at pH 7, simulating the esophageal environment, to assess the pH responsiveness of the coating formulations. For both formulations, the effect of pH on the development time was not significant.

[0239] The gastroretentive systems coated with both formulations were then coated with a Eudragit E based pH responsive coating. The processability, appearance and development time of the coated gastroretentive systems were evaluated (as shown in Figure 13 and Table 10). The gastroretentive systems coated with hydrolysate containing formulation 1 showed cracks in the shell after pan-coating process. The gastroretentive systems coated with formulation 2 showed no cracks and slightly higher coating weight gain, indicating better coating adhesion.

[0240] In Figure 13, the development time for both coating formulations at both pH 3 and pH 7 is shown. In the gastroretentive system coated with formulation 1, no pH responsive effect was observed for coating sublots A, B and C. However, in the gastroretentive system coated with formulation 2, pH responsive effect was observed for all sublots.

[0241] For example, for Formulation 2 Sublot C, the mean deployment time was 36±11 minutes at pH 3 and 87±12 minutes at pH 7. This represents a two-fold difference in deployment time at pH 7 compared to pH 3 for this group of gastroretentive systems. Such pH-responsive behavior of the coated, covered gastroretentive system allows for rapid deployment in the gastric environment while sufficiently delaying deployment at esophageal pH.

[0242] [Table 10]

[0243] Test Method Spreading Test: Spreading time is defined as the time it takes for the gastroretentive system to assume an open configuration. To measure the spread time, the gastroretentive dosage form may be placed in 35 mL of a particular medium in an experimental rocking apparatus. Specifically, a 450 mL glass jar with a diameter of 80 mm, a height of 94 mm, and a lid lined with polytetrafluoroethylene was used. Once the gastroretentive dosage form was placed in the jar containing the 35 mL of medium, the jar was sealed, inverted, and immediately placed in the experimental rocking apparatus. The experimental rocking apparatus was set to 30 cycles per minute.

[0244] Depending on the desired test conditions, various culture media were used. In some tests, phosphate buffered saline solutions were used at either pH 7.0 (to mimic the pH conditions of the human esophagus) or pH 3.0 (to mimic the slightly acidic pH conditions of the human stomach). The pH 7.0 solution was prepared by dissolving 1.36 grams of anhydrous potassium dihydrogen phosphate and 8.41 grams of sodium chloride in water, adjusting to pH 7.0 with sodium hydroxide, and diluting to a final volume of 1.0 liter with water. The pH 3.0 solution was prepared by dissolving 1.36 grams of anhydrous potassium dihydrogen phosphate and 8.41 grams of sodium chloride in water, adjusting to pH 3.0 with hydrochloric acid, and diluting to a final volume of 1.0 liter with water.

[0245] The spreading test was also carried out using a culture of hydrochloric acid (pH 1.5) containing sodium chloride to mimic the highly acidic pH conditions of the human stomach. This solution was prepared by dissolving 9.00 grams of sodium chloride in a pH 1.5 hydrochloric acid solution to a final volume of 1.0 liter.

[0246] Tackiness on Storage: To measure tackiness, the coated capsules were placed in containers and stored for a specified period of time (i.e., one week to one month). Five to ten coated capsules were placed in each container and sealed with a hand twist-open cap with an integral foil liner. The containers used were 40cc or 60cc wide-mouth pharmaceutical round bottles (Drug Plastics Corp.). The coated capsules were kept in the containers in a controlled chamber (e.g., humidity, temperature, etc.). Specific storage conditions tested included low relative humidity (i.e., less than 40%), no rayon coil, room temperature, high relative humidity (i.e., greater than 70%), no rayon coil, room temperature, ambient relative humidity and with rayon coil, and 40°C with 75% relative humidity. Tackiness on storage was evaluated at the end of the specified period by opening the cap and visually observing the tackiness behavior of the stored coated capsules with the bottles inverted.

[0247] Drop Test (Friability Test): Coated capsules were dropped through a 2 foot long polyvinyl chloride (PVC) tube onto a hard bench surface. The PVC tube had a diameter of approximately 1.5 inches. Each coated capsule was dropped 5 to 10 times onto each rounded end. After each drop, the coated capsules were closely examined under a microscope to observe for delamination or cracks.

[0248] Friction Testing: Approximately 3 inch by 3 inch squares were cut from sausage skins (LEM products smoked clear edible collagen skins) and soaked in deionized water for at least 30 minutes. One square was cut for each sample to be tested. An Instron tensile testing instrument (Model 3342), shown in Figure 14A, was used with a static friction coefficient fixture (standard attachment) and a 10N load cell. A custom sled was used to hold two capsules in a parallel orientation in direct contact with the skin faces. The custom sled is shown in Figures 14B and 14C.

[0249] For each capsule sample, a square of water-soaked skin was placed on the test surface and flattened by wiping with a rubber spatula from the center to each end to remove any air bubbles and excess liquid located between the skin and the test surface. Two capsules were inserted into slots in a custom machined sled. The sled was attached to a nylon string. The string was threaded through a fixture pulley to the hook of a 10N load cell attached to an Instron crosshead. The sled was placed over the skin in an orientation such that only two capsules were in contact with the skin and the direction of movement was axial with respect to the capsules. The sled was left in place for a specified period of time. The sled was generally left in place for 2-10 minutes to reflect various swallowing times.

[0250] At the end of the hold time, the crosshead was moved upward at a speed of 150 mm / min, pulling the sled forward on the test surface until it reached a travel distance of 15 mm. The peak force that moved the sled was measured. The static friction coefficient for each pair of capsules was calculated by dividing the peak force by the normal force exerted by gravity on the sled and capsule (the normal force exerted by gravity on the sled and capsule was determined based on the weight of the sled and capsule). The static friction coefficients for each capsule group were averaged and compared.

[0251] Embodiment The present invention will be further illustrated by the following embodiments, the features of each of which may, where necessary and feasible, be combined with any of the other embodiments.

[0252] Embodiment 1. A gastric retention dosage form comprising a gastric retention system in a folded configuration, a capsule encapsulating the gastric retention system in the folded configuration, and a coating on the capsule, the gastric retention dosage form configured to release the gastric retention system in a patient's stomach and cause the gastric retention system to assume an open configuration.

[0253] Embodiment 2. The gastric retention dosage form of embodiment 1, wherein the gastric retention dosage form causes the gastric retention system to assume the open configuration within a first time upon exposure to an aqueous pH 7.0 environment, the first time being longer than a second time during which the uncoated gastric retention dosage form causes the gastric retention system to assume the open configuration upon exposure to the aqueous pH 7.0 environment for an uncoated gastric retention dosage form comprising an uncoated capsule.

[0254] Embodiment 3. The gastric retention dosage form of embodiment 2, wherein the first time period is at least 1 minute longer than the second time period.

[0255] Embodiment 4. The gastric retention dosage form of embodiment 2, wherein the gastric retention dosage form causes the gastric retention system to adopt the open configuration within at least 20 minutes upon exposure to the aqueous pH 7.0 environment.

[0256] Embodiment 5. The gastric retention dosage form of embodiment 2 or 4, wherein the gastric retention dosage form causes the gastric retention system to adopt the open configuration within at least 30 minutes upon exposure to the aqueous pH 7.0 environment.

[0257] Embodiment 6: The gastric retention dosage form of any one of embodiments 1 to 5, wherein the gastric retention dosage form causes the gastric retention system to assume the open configuration within a third time upon exposure to an aqueous pH 3.0 environment, the third time being longer than a fourth time during which the uncoated gastric retention dosage form causes the gastric retention system to assume the open configuration upon exposure to an aqueous pH 3.0 environment for an uncoated gastric retention dosage form comprising an uncoated capsule.

[0258] Embodiment 7. The gastric retention dosage form of embodiment 6, wherein the third time period is at least 15 seconds longer than the fourth time period.

[0259] Embodiment 8. The gastric retention dosage form of embodiment 6 or 7, wherein the gastric retention dosage form causes the gastric retention system to adopt the open configuration in less than 30 minutes upon exposure to the aqueous pH 3.0 environment.

[0260] Embodiment 9. The gastric retention dosage form of any one of embodiments 6 to 8, wherein the gastric retention dosage form causes the gastric retention system to adopt the open configuration in less than 15 minutes upon exposure to the aqueous pH 3.0 environment.

[0261] Embodiment 10. The gastric retention dosage form of any one of embodiments 1 to 9, comprising a sheath, said sheath surrounding at least a portion of said gastric retention system in said folded configuration.

[0262] Embodiment 11. The gastric retention dosage form of any one of embodiments 1 to 10, wherein the coating comprises a reverse enteric polymer.

[0263] Embodiment 12. The gastric retention dosage form of embodiment 11, wherein the reverse enteric polymer comprises a polymethacrylate-based polymer.

[0264] Embodiment 13. The gastric retention dosage form of any one of embodiments 1 to 12, wherein the coating comprises an anti-adherent agent.

[0265] Embodiment 14. The gastric retention dosage form of embodiment 13, wherein the anti-adherent agent comprises at least one of talc or magnesium stearate.

[0266] Embodiment 15. The gastric retention dosage form of any one of embodiments 1 to 14, wherein the coating comprises a plasticizer.

[0267] Embodiment 16. The gastric retention dosage form of embodiment 15, wherein the plasticizer comprises at least one of a phthalate, phosphate, citrate, tartrate, adipate, sebacate, sulfonamide, succinate, glycolate, glycerolate, benzoate, myristate, polyethylene glycol, phenyl halide, or poloxamer.

[0268] Embodiment 17. The gastric retention dosage form of embodiment 15 or 16, wherein the plasticizer comprises at least one of triacetin or dibutyl sebacate.

[0269] Embodiment 18. The gastric retention dosage form of any one of embodiments 1 to 17, wherein the coating comprises a hydration aid.

[0270] Embodiment 19. The gastric retention dosage form of embodiment 18, wherein the hydration aid comprises at least one of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, mannitol, or hydroxypropyl methylcellulose.

[0271] Embodiment 20. The gastric retention dosage form of any one of embodiments 1 to 19, wherein the coating comprises 50-95% by weight of a reverse enteric polymer.

[0272] Embodiment 21. The gastric retention dosage form of any one of embodiments 1 to 20, wherein the coating comprises 3-25% by weight of an anti-adherent agent.

[0273] Embodiment 22. The gastric retention dosage form of any one of embodiments 1 to 21, wherein the coating comprises 1 to 20% by weight of a plasticizer.

[0274] Embodiment 23. The gastric retention dosage form of any one of embodiments 1 to 22, wherein the coating comprises 3-35% by weight of a hydration aid.

[0275] Embodiment 24. The gastric retention dosage form of embodiment 10, wherein the sheath comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

[0276] Embodiment 25. The gastric retention dosage form of any one of embodiments 1 to 24, wherein the capsule comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

[0277] Embodiment 26. The gastric retention dosage form of any one of embodiments 1 to 25, wherein the gastric retention dosage form is used to treat a patient.

[0278] Embodiment 27 The gastric retention dosage form of embodiment 26, wherein the patient is a human.

[0279] Embodiment 28. A coating for an encapsulated gastroretentive system, said coating comprising 50-95% by weight of a reverse enteric polymer, 3-25% by weight of an anti-adherent agent, and 1-20% by weight of a plasticizer.

[0280] Embodiment 29. The coating of embodiment 28, wherein the coating is on a surface of a capsule to form a coated capsule.

[0281] Embodiment 30. The coating of embodiment 29, wherein the coated capsule encapsulates a gastroretentive system to form a gastroretentive dosage form configured to release the gastroretentive system in the patient's stomach and cause the gastroretentive system to assume an open configuration.

[0282] Embodiment 31. The coating of any one of embodiments 28-30 comprising 5-35 wt.% of a hydration adjuvant.

[0283] Embodiment 32. The coating of embodiment 31, wherein the hydration adjuvant comprises at least one of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, mannitol, or hydroxypropyl methylcellulose.

[0284] Embodiment 33. The coating of any one of embodiments 28-32, wherein the reverse enteric polymer comprises a polymethacrylate-based polymer.

[0285]

[0041] Embodiment 34. The coating of any one of embodiments 28-33, wherein the anti-adherent agent comprises at least one of talc or magnesium stearate.

[0286] Embodiment 35. The coating of any one of embodiments 28-34, wherein the plasticizer comprises a phthalate, phosphate, citrate, tartrate, adipate, sebacate, sulfonamide, succinate, glycolate, glycerolate, benzoate, myristate, polyethylene glycol, phenyl halide, or poloxamer.

[0287]

[0041] Embodiment 36. The coating of any one of embodiments 28-35, wherein the plasticizer comprises at least one of triacetin and dibutyl sebacate.

[0288] Embodiment 37. The coating of any one of embodiments 28-36, wherein the coating is soluble in an aqueous solution.

[0289] Embodiment 38. The coating of any one of embodiments 28-37, wherein the coating is soluble in an organic solvent.

[0290] Embodiment 39. The coating of any one of embodiments 30-38, wherein the gastric retention dosage form causes the gastric retention system to assume the open configuration within a first time upon exposure to an aqueous pH 7.0 environment, the first time being longer than a second time during which the uncoated gastric retention dosage form causes the gastric retention system to assume the open configuration upon exposure to the aqueous pH 7.0 environment for an uncoated gastric retention dosage form comprising an uncoated capsule.

[0291] Embodiment 40. The coating of embodiment 39, wherein the first period of time is at least 1 minute longer than the second period of time.

[0292] Embodiment 41. The gastroretentive dosage form of embodiment 39 or 40, wherein the coating causes the gastroretentive system to adopt the open configuration within at least 20 minutes upon exposure to the aqueous pH 7.0 environment.

[0293] Embodiment 42. The gastroretentive dosage form of any one of embodiments 39-41, wherein the coating causes the gastroretentive system to assume the open configuration within at least 30 minutes upon exposure to the aqueous pH 7.0 environment.

[0294] Embodiment 43. The coating of any one of embodiments 30-42, wherein the gastric retention dosage form causes the gastric retention system to assume the open configuration within a third time upon exposure to an aqueous pH 3.0 environment, the third time being longer than a fourth time during which the uncoated gastric retention dosage form causes the gastric retention system to assume the open configuration upon exposure to an aqueous pH 3.0 environment for an uncoated gastric retention dosage form comprising an uncoated capsule.

[0295] Embodiment 44. The coating of embodiment 43, wherein the third period of time is at least 15 seconds longer than the fourth period of time.

[0296] Embodiment 45. The gastroretentive dosage form of embodiment 43 or 44, wherein the coating causes the gastroretentive system to adopt the open configuration in less than 30 minutes upon exposure to the aqueous pH 3.0 environment.

[0297] Embodiment 46. The gastroretentive dosage form according to any one of embodiments 43 to 45, wherein the coating causes the gastroretentive system to adopt the open configuration in less than 15 minutes upon exposure to the aqueous pH 3.0 environment.

[0298] Embodiment 47. A gastric retention dosage form comprising a coating according to any one of embodiments 30 to 46, for use in treating a patient.

[0299] Embodiment 48. The gastric retention dosage form of embodiment 47, wherein the patient is a human.

[0300] Embodiment 49. A method for producing a gastric retention dosage form, the method comprising: encapsulating the gastroretentive system in a folded form with a capsule; and coating the capsule with a reverse enteric coating to form a gastroretentive dosage form.

[0301]

[0046] Embodiment 50. The method of embodiment 49, comprising constraining the gastroretentive system in the folded form with a sheath prior to encapsulation.

[0302]

[0046] Embodiment 51. The method of embodiment 49 or 50, wherein coating the capsule with a reverse enteric coating comprises pan-coating the capsule.

[0303] Embodiment 52. The method of any one of embodiments 49-51, wherein the reverse enteric coating comprises a reverse enteric polymer, an anti-tack agent, and a plasticizer.

[0304]

[0081] Embodiment 53. The method of embodiment 52, wherein the anti-adherent agent comprises at least one of talc or magnesium stearate.

[0305] Embodiment 54. The method of embodiment 52 or 53, wherein the plasticizer comprises at least one of a phthalate, phosphate, citrate, tartrate, adipate, sebacate, sulfonamide, succinate, glycolate, glycerolate, benzoate, myristate, polyethylene glycol, phenyl halide, or poloxamer.

[0306]

[0081] Embodiment 55. The method of any one of embodiments 52-54, wherein the plasticizer comprises at least one of triacetin or dibutyl sebacate.

[0307] Embodiment 56. The method of any one of embodiments 49-55, wherein the reverse enteric coating comprises a hydration aid.

[0308] Embodiment 57. The method of embodiment 56, wherein the hydration adjuvant comprises at least one of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, mannitol, or hydroxypropyl methylcellulose.

[0309] Embodiment 58. The method of any one of embodiments 49-57, wherein the capsule comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

[0310]

[0046] Embodiment 59. The method of embodiment 50, wherein the sheath comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

[0311]

[0046] Embodiment 60. The method of any one of embodiments 49-59, wherein the gastroretentive dosage form is configured to release the gastroretentive system in the patient's stomach and cause the gastroretentive system to assume an open configuration.

[0312] Embodiment 61. The method of embodiment 60, wherein the gastric retention dosage form causes the gastric retention system to assume the open configuration within a first time upon exposure to an aqueous pH 7.0 environment, and the first time is longer than a second time during which the uncoated gastric retention dosage form causes the gastric retention system to assume the open configuration upon exposure to the aqueous pH 7.0 environment for an uncoated gastric retention dosage form comprising an uncoated capsule.

[0313]

[0082] Embodiment 62. The method of embodiment 61, wherein the first period of time is at least 1 minute longer than the second period of time.

[0314] Embodiment 63. The method of embodiment 60 or 61, wherein the gastroretentive dosage form causes the gastroretentive system to adopt the open configuration within at least 20 minutes upon exposure to the aqueous pH 7.0 environment.

[0315] Embodiment 64. The method of any one of embodiments 60-63, wherein the gastroretentive dosage form, upon exposure to the aqueous pH 7.0 environment, causes the gastroretentive system to adopt the open configuration within at least 30 minutes.

[0316] Embodiment 65. The method of any one of embodiments 60 to 64, wherein the gastric retention dosage form causes the gastric retention system to assume the open configuration within a third time upon exposure to an aqueous pH 3.0 environment, the third time being longer than a fourth time during which the uncoated gastric retention dosage form causes the gastric retention system to assume the open configuration upon exposure to the aqueous pH 3.0 environment for an uncoated gastric retention dosage form comprising an uncoated capsule.

[0317]

[0071] Embodiment 66. The method of embodiment 65, wherein the third period of time is at least 15 seconds longer than the fourth period of time.

[0318] Embodiment 67. The method of embodiment 65 or 66, wherein the gastroretentive dosage form, upon exposure to the aqueous pH 3.0 environment, causes the gastroretentive system to adopt the open configuration in less than 30 minutes.

[0319] Embodiment 68. The method of any one of embodiments 65-67, wherein the gastroretentive dosage form, upon exposure to the aqueous pH 3.0 environment, causes the gastroretentive system to adopt the open configuration in less than 15 minutes.

[0320] Embodiment 69. A gastric retention dosage form produced using the method of any one of embodiments 49-68, for use in treating a patient.

[0321] Embodiment 70. The gastric retention dosage form of embodiment 69, wherein the patient is a human.

[0322] Embodiment 71. A coated dosage form comprising a dosage form and a coating comprising a reverse enteric polymer coating the dosage form;

[0323]

number

[0324] A coated dosage form comprising:

[0325] Embodiment 72. The coated dosage form of embodiment 71, wherein the coating comprises magnesium stearate.

[0326] Embodiment 73. The coated dosage form of embodiment 71 or 72, wherein the dosage form comprises one of a tablet, a capsule or a coated gastroretentive system.

[0327] Embodiment 74. The coated dosage form of embodiment 73, wherein the dosage form comprises a capsule.

[0328] Embodiment 75. The coated dosage form of embodiment 74, wherein the capsule encapsulates a gastroretentive system.

[0329] Embodiment 76. The coated dosage form of any one of embodiments 71-75, wherein the static coefficient of friction of the coated dosage form is less than 0.3.

[0330] Embodiment 77. The coated dosage form of any one of embodiments 71-76, wherein the static coefficient of friction of the coated dosage form is less than 0.2.

[0331] Embodiment 78. The coated dosage form of any one of embodiments 71-77, wherein the static coefficient of friction of the coated dosage form is less than 0.1.

[0332] EMBODIMENT 79

[0333]

number

[0334] The coated dosage form according to any one of embodiments 71 to 78, wherein

[0335] Embodiment 80. The coated dosage form of any one of embodiments 71-79, wherein the static coefficient of friction is at least 0.08 less than the static coefficient of friction of the uncoated dosage form.

[0336] Embodiment 81. The coated dosage form of any one of embodiments 71-80, wherein the static coefficient of friction of the coated dosage form is at least 0.15 less than the static coefficient of friction of an uncoated dosage form.

[0337] Embodiment 82. The coated dosage form of any one of embodiments 71-81, wherein the static coefficient of friction of the coated dosage form is at least 0.2 less than the static coefficient of friction of an uncoated dosage form.

[0338] Embodiment 83. The coated dosage form of any one of embodiments 71-82, wherein the reverse enteric polymer comprises a polymethacrylate.

[0339] Embodiment 84. The coated dosage form of any one of embodiments 71 to 83, wherein the coating comprises 10 to 50% by weight of a reverse enteric polymer.

[0340] Embodiment 85. The coated dosage form of any one of embodiments 71-84, wherein the coating comprises an anti-adherent agent.

[0341] Embodiment 86. The coated dosage form of any one of embodiments 71-85, wherein the anti-adhesive agent comprises talc.

[0342] Embodiment 87. The coated dosage form of embodiment 85 or 86, wherein the coating comprises 5 to 30% by weight of an anti-adherent agent.

[0343] Unless otherwise specified, all terminology, notations, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or quick reference, and the inclusion of such definitions herein should not necessarily be construed as implying a substantial difference beyond what is commonly understood in the art.

[0344] Reference herein to "about" a value or parameter includes (and describes) variations that are directed to the value or parameter itself. For example, a statement about "about X" includes a statement of "X."

[0345] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly dictates otherwise. As used herein, the term "and / or" is also understood to refer to and include any and all possible combinations of one or more of the associated listed items. Further, as used herein, the terms "includes," "including," "comprises," and / or "comprising" specify the presence of stated features, integers, steps, operations, components, elements, and / or units, but do not exclude the presence or addition of one or more other features, integers, steps, operations, components, elements, units, and / or groups thereof.

[0346] In this application, several numerical ranges are disclosed by letters and numbers. Because the disclosure can be practiced with the disclosed numerical ranges, the disclosed numerical ranges inherently support any range or value within the disclosed numerical ranges, including the endpoints, even if the exact range limitations are not literally stated in the specification.

[0347] The foregoing description has been described with reference to specific embodiments for purposes of explanation. However, the above exemplary discussion is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of the above teachings. The embodiments have been chosen and described in order to best explain the principles of the technology and their practical applications. Others skilled in the art may thereby best utilize various embodiments with various modifications as adapted to the technology and the particular anticipated use.

[0348] Although the present disclosure and embodiments have been fully described with reference to the accompanying drawings, it should be noted that various changes and modifications will become apparent to those skilled in the art, and such changes and modifications should be understood to be included within the scope of the present disclosure and embodiments as defined by the claims.

Claims

1. A gastric retention dosage form, the gastric retention dosage form comprising: A gastroretentive system in a folded form; a capsule encapsulating the gastroretentive system in the folded configuration; and a coating on the capsule; The gastroretentive dosage form is configured to release the gastroretentive system in a patient's stomach, causing the gastroretentive system to assume an open configuration.

2. 2. The gastric retention dosage form of claim 1, wherein the gastric retention dosage form causes the gastric retention system to assume the open configuration within a first time upon exposure to an aqueous pH 7.0 environment, the first time being longer than a second time during which the uncoated gastric retention dosage form causes the gastric retention system to assume the open configuration upon exposure to the aqueous pH 7.0 environment for an uncoated gastric retention dosage form comprising an uncoated capsule.

3. 3. The gastric retention dosage form of claim 2, wherein the first time period is at least 1 minute longer than the second time period.

4. 3. The gastric retention dosage form of claim 2, wherein the gastric retention dosage form causes the gastric retention system to assume the open configuration within at least 20 minutes upon exposure to the aqueous pH 7.0 environment.

5. 5. The gastric retention dosage form of claim 2 or 4, wherein the gastric retention dosage form causes the gastric retention system to assume the open configuration within at least 30 minutes upon exposure to the aqueous pH 7.0 environment.

6. 6. The gastric retention dosage form of any one of claims 1 to 5, wherein the gastric retention dosage form causes the gastric retention system to assume the open configuration within a third time upon exposure to an aqueous pH 3.0 environment, the third time being longer than a fourth time during which the uncoated gastric retention dosage form causes the gastric retention system to assume the open configuration upon exposure to an aqueous pH 3.0 environment for an uncoated gastric retention dosage form comprising an uncoated capsule.

7. The gastric retention dosage form of claim 6 , wherein the third time period is at least 15 seconds longer than the fourth time period.

8. 8. The gastric retention dosage form of claim 6 or 7, wherein the gastric retention dosage form causes the gastric retention system to adopt the open configuration in less than 30 minutes upon exposure to the aqueous pH 3.0 environment.

9. The gastroretentive dosage form of any one of claims 6 to 8, wherein the gastroretentive dosage form causes the gastroretentive system to adopt the open configuration in less than 15 minutes upon exposure to the aqueous pH 3.0 environment.

10. The gastroretentive dosage form of any one of claims 1 to 9, comprising a sheath, said sheath surrounding at least a portion of said gastroretentive system in said folded configuration.

11. The gastroretentive dosage form of any one of claims 1 to 10, wherein the coating comprises a reverse enteric polymer.

12. The gastric retention dosage form of claim 11 , wherein the reverse enteric polymer comprises a polymethacrylate-based polymer.

13. The gastroretentive dosage form of any one of claims 1 to 12, wherein the coating comprises an anti-adherent agent.

14. 14. The gastric retention dosage form of claim 13, wherein the anti-adherent agent comprises at least one of talc or magnesium stearate.

15. The gastroretentive dosage form of any one of claims 1 to 14, wherein the coating comprises a plasticizer.

16. 16. The gastric retentive dosage form of claim 15, wherein the plasticizer comprises at least one of phthalates, phosphates, citrates, tartrates, adipates, sebacates, sulfonamides, succinates, glycolates, glycerol salts, benzoates, myristates, polyethylene glycols, phenyl halides, or poloxamers.

17. 17. The gastric retaining dosage form of claim 15 or 16, wherein the plasticizer comprises at least one of triacetin or dibutyl sebacate.

18. The gastroretentive dosage form of any one of claims 1 to 17, wherein the coating comprises a hydration aid.

19. 20. The gastric retention dosage form of claim 18, wherein the hydration aid comprises at least one of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, mannitol, or hydroxypropyl methylcellulose.

20. The gastroretentive dosage form of any one of claims 1 to 19, wherein the coating comprises 50 to 95% by weight of a reverse enteric polymer.

21. The gastroretentive dosage form of any one of claims 1 to 20, wherein the coating comprises 3 to 25% by weight of an anti-adherent agent.

22. The gastroretentive dosage form of any one of claims 1 to 21, wherein the coating comprises 1 to 20% by weight of a plasticizer.

23. The gastroretentive dosage form of any one of claims 1 to 22, wherein the coating comprises 3 to 35% by weight of a hydration aid.

24. 11. The gastric retention dosage form of claim 10, wherein the sheath comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

25. 25. The gastroretentive dosage form of any one of claims 1 to 24, wherein the capsule comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

26. The gastroretentive dosage form of any one of claims 1 to 25, wherein the gastroretentive dosage form is used to treat a patient.

27. The gastric retention dosage form of claim 26, wherein the patient is a human.

28. 1. A coating for an encapsulated gastroretentive system, the coating comprising: 50-95% by weight of a reverse enteric polymer; 3 to 25% by weight of an anti-blocking agent, and A coating comprising 1 to 20 weight percent of a plasticizer.

29. 30. The coating of claim 28, wherein the coating is on a surface of a capsule to form a coated capsule.

30. 30. The coating of claim 29, wherein the coated capsule encapsulates a gastroretentive system to form a gastroretentive dosage form configured to release the gastroretentive system in a patient's stomach and cause the gastroretentive system to assume an open configuration.

31. 31. The coating of any one of claims 28 to 30 comprising 5 to 35% by weight of a hydration adjuvant.

32. 32. The coating of claim 31, wherein the hydration aid comprises at least one of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, mannitol, or hydroxypropyl methylcellulose.

33. The coating of any one of claims 28 to 32, wherein the reverse enteric polymer comprises a polymethacrylate-based polymer.

34. The coating of any one of claims 28 to 33, wherein the anti-adherent agent comprises at least one of talc or magnesium stearate.

35. 35. The coating of any one of claims 28 to 34, wherein the plasticizer comprises a phthalate, a phosphate, a citrate, a tartrate, an adipate, a sebacate, a sulfonamide, a succinate, a glycolate, a glycerol salt, a benzoate, a myristate, a polyethylene glycol, a phenyl halide, or a poloxamer.

36. The coating of any one of claims 28 to 35, wherein the plasticizer comprises at least one of triacetin and dibutyl sebacate.

37. The coating of any one of claims 28 to 36, wherein the coating is soluble in an aqueous solution.

38. The coating of any one of claims 28 to 37, wherein the coating is soluble in organic solvents.

39. 39. The coating of any one of claims 30 to 38, wherein the gastroretentive dosage form causes the gastroretentive system to assume the open configuration within a first time upon exposure to an aqueous pH 7.0 environment, the first time being longer than a second time during which the uncoated gastroretentive dosage form causes the gastroretentive system to assume the open configuration upon exposure to the aqueous pH 7.0 environment for an uncoated gastroretentive dosage form comprising an uncoated capsule.

40. 40. The coating of claim 39, wherein the first time period is at least 1 minute longer than the second time period.

41. 41. The coating of claim 39 or 40, wherein the gastroretentive dosage form, upon exposure to the aqueous pH 7.0 environment, causes the gastroretentive system to adopt the open configuration within at least 20 minutes.

42. 42. The coating of any one of claims 39 to 41, wherein the gastroretentive dosage form, upon exposure to the aqueous pH 7.0 environment, causes the gastroretentive system to adopt the open configuration within at least 30 minutes.

43. 43. The coating of any one of claims 30 to 42, wherein the gastroretentive dosage form causes the gastroretentive system to assume the open configuration within a third time upon exposure to an aqueous pH 3.0 environment, the third time being longer than a fourth time during which the uncoated gastroretentive dosage form causes the gastroretentive system to assume the open configuration upon exposure to an aqueous pH 3.0 environment for an uncoated gastroretentive dosage form comprising an uncoated capsule.

44. 44. The coating of claim 43, wherein the third time period is at least 15 seconds longer than the fourth time period.

45. 45. The coating of claim 43 or 44, wherein the gastroretentive dosage form, upon exposure to the aqueous pH 3.0 environment, causes the gastroretentive system to adopt the open configuration in less than 30 minutes.

46. 46. ​​The coating of any one of claims 43 to 45, wherein the gastroretentive dosage form, upon exposure to the aqueous pH 3.0 environment, causes the gastroretentive system to adopt the open configuration in less than 15 minutes.

47. A gastroretentive dosage form comprising a coating according to any one of claims 30 to 46 for use in treating a patient.

48. The gastric retention dosage form of claim 47, wherein the patient is a human.

49. 1. A method for producing a gastric retentive dosage form, the method comprising: encapsulating the gastroretentive system in a folded form with a capsule; and and coating the capsule with a reverse enteric coating to form a gastroretentive dosage form.

50. 50. The method of claim 49, comprising sheathing the gastroretentive system in the folded form prior to encapsulation.

51. 51. The method of claim 49 or 50, wherein coating the capsule with a reverse enteric coating comprises pan-coating the capsule.

52. 52. The method of any one of claims 49 to 51, wherein the reverse enteric coating comprises a reverse enteric polymer, an anti-tack agent, and a plasticizer.

53. 53. The method of claim 52, wherein the anti-adherent agent comprises at least one of talc or magnesium stearate.

54. 54. The method of claim 52 or 53, wherein the plasticizer comprises at least one of a phthalate, a phosphate, a citrate, a tartrate, an adipate, a sebacate, a sulfonamide, a succinate, a glycolate, a glycerol salt, a benzoate, a myristate, a polyethylene glycol, a phenyl halide, or a poloxamer.

55. 55. The method of any one of claims 52 to 54, wherein the plasticizer comprises at least one of triacetin or dibutyl sebacate.

56. 56. The method of any one of claims 49 to 55, wherein the reverse enteric coating comprises a hydration aid.

57. 57. The method of claim 56, wherein the hydration adjuvant comprises at least one of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, mannitol, or hydroxypropyl methylcellulose.

58. 58. The method of any one of claims 49 to 57, wherein the capsule comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

59. 51. The method of claim 50, wherein the sheath comprises at least one of gelatin, hydroxypropyl methylcellulose, or pullulan.

60. 60. The method of any one of claims 49 to 59, wherein the gastroretentive dosage form is configured to release the gastroretentive system in the patient's stomach and cause the gastroretentive system to assume an open configuration.

61. 61. The method of claim 60, wherein the gastroretentive dosage form causes the gastroretentive system to assume the open configuration within a first time upon exposure to an aqueous pH 7.0 environment, the first time being longer than a second time for an uncoated gastroretentive dosage form comprising an uncoated capsule that causes the gastroretentive system to assume the open configuration upon exposure to the aqueous pH 7.0 environment.

62. 62. The method of claim 61, wherein the first period of time is at least one minute longer than the second period of time.

63. 62. The method of claim 60 or 61, wherein the gastroretentive dosage form, upon exposure to the aqueous pH 7.0 environment, causes the gastroretentive system to assume the open configuration within at least 20 minutes.

64. 64. The method of any one of claims 60 to 63, wherein the gastroretentive dosage form, upon exposure to the aqueous pH 7.0 environment, causes the gastroretentive system to adopt the open configuration within at least 30 minutes.

65. 65. The method of any one of claims 60 to 64, wherein the gastroretentive dosage form causes the gastroretentive system to assume the open configuration within a third time upon exposure to an aqueous pH 3.0 environment, the third time being longer than a fourth time during which the uncoated gastroretentive dosage form causes the gastroretentive system to assume the open configuration upon exposure to the aqueous pH 3.0 environment for an uncoated gastroretentive dosage form comprising an uncoated capsule.

66. 66. The method of claim 65, wherein the third period of time is at least 15 seconds longer than the fourth period of time.

67. 67. The method of claim 65 or 66, wherein the gastroretentive dosage form, upon exposure to the aqueous pH 3.0 environment, causes the gastroretentive system to assume the open configuration in less than 30 minutes.

68. 68. The method of any one of claims 65 to 67, wherein the gastroretentive dosage form, upon exposure to the aqueous pH 3.0 environment, causes the gastroretentive system to adopt the open configuration in less than 15 minutes.

69. A gastroretentive dosage form produced using the method of any one of claims 49 to 68 for use in treating a patient.

70. The gastric retention dosage form of claim 69, wherein the patient is a human.

71. A coated dosage form, said coated dosage form comprising: Dosage form, and a coating comprising a reverse enteric polymer coating said dosage form; [0010] A coated dosage form comprising:

72. 72. The coated dosage form of claim 71, wherein the coating comprises magnesium stearate.

73. 73. The coated dosage form of claim 71 or 72, wherein the dosage form comprises one of a tablet, a capsule, or an enrobed gastroretentive system.

74. 74. The coated dosage form of claim 73, wherein the dosage form comprises a capsule.

75. 75. The coated dosage form of claim 74, wherein the capsule encapsulates a gastroretentive system.

76. 76. The coated dosage form of any one of claims 71 to 75, wherein the static friction coefficient of the coated dosage form is less than 0.

3.

77. 77. The coated dosage form of any one of claims 71 to 76, wherein the static friction coefficient of the coated dosage form is less than 0.

2.

78. 78. The coated dosage form of any one of claims 71 to 77, wherein the static friction coefficient of the coated dosage form is less than 0.

1. 【Request 79】 【Number 2】 79. The coated dosage form of any one of claims 71 to 78, wherein

80. 80. The coated dosage form of any one of claims 71 to 79, wherein the static coefficient of friction is at least 0.08 less than the static coefficient of friction of the uncoated dosage form.

81. 81. The coated dosage form of any one of claims 71 to 80, wherein the static coefficient of friction of the coated dosage form is at least 0.15 less than the static coefficient of friction of an uncoated dosage form.

82. 82. The coated dosage form of any one of claims 71 to 81, wherein the static coefficient of friction of the coated dosage form is at least 0.2 less than the static coefficient of friction of an uncoated dosage form.

83. The coated dosage form of any one of claims 71 to 82, wherein the reverse enteric polymer comprises a polymethacrylate.

84. 84. The coated dosage form of any one of claims 71 to 83, wherein the coating comprises 10 to 50% by weight of a reverse enteric polymer.

85. 85. The coated dosage form of any one of claims 71 to 84, wherein the coating comprises an anti-adherent agent.

86. 86. The coated dosage form of any one of claims 71 to 85, wherein the anti-adherent agent comprises talc.

87. 87. The coated dosage form of claim 85 or 86, wherein the coating comprises 5-30% by weight of an anti-adherent agent.

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